bluuebunny/crossref_metadata_2025 huggingface dataset:
Imatinib decreases germ cell survival and germline stem cell proliferation in rodent testis ex vivo and in vitro
Authors: Eggert Anna , Laasanen Sini , Nurmio Mirja , Wahlgren Aida , Jahnukainen Kirsi , Eerola Kim , Nieminen Miisael , Olotu Opeyemi , Kotaja Noora , Mäkelä Juho‐Antti , Toppari Jorma
Published: October 2024

Background

Imatinib and dasatinib are tyrosine kinase inhibitors (TKIs) increasingly used to treat several diseases in both children and adults at fertile age. We have previously shown that imatinib has adverse effects on developing testis, and imatinib‐treated male patients have been reported to have reduced sperm counts. However, the cellular level effects of imatinib and dasatinib on adult male germ cells and germline stem cells (mGSCs) have not been thoroughly investigated.

Objectives

To analyze whether imatinib or dasatinib exposure ex vivo and in vitro is harmful to adult male rodent germ cells and mGSCs.

Materials and methods

Seminiferous tubule segments of adult male mouse or rat were cultured in the presence or the absence of imatinib or dasatinib. Stage‐specific effects were monitored by 3H‐thymidine incorporation assay (DNA synthesis), immunohistochemistry (cleaved Caspase‐3; apoptosis), immunofluorescence (KI67, GFRα1, STRA8, c‐KIT, LIN28A; proliferation and spermatogonial differentiation) and flow cytometry (Hoechst). Mouse mGSCs were exposed to imatinib and dasatinib to study proliferation, apoptosis, and differentiation.

Results

Imatinib decreased stage‐specific DNA synthesis, and induced apoptosis in cultured rat seminiferous tubule segments. Imatinib also had an adverse effect on mGSC proliferation both in vitro and ex vivo, but did not induce cell death in cultured mGSCs. Imatinib did not impinge on induction of spermatogonial differentiation but suppressed c‐KIT expression in nascent differentiating spermatogonia, providing a plausible mechanism for its pro‐apoptotic function in spermatogenic cells. Clinically relevant doses of dasatinib did not induce apoptosis in seminiferous tubules but decreased mGSC colony growth in vitro.

Conclusions

Imatinib exposure ex vivo and in vitro impinges on male rodent germ cell proliferation and survival. The plausible mechanism in spermatogenic cells is the inhibition of SCF/c‐KIT signaling, and reduced expression of c‐KIT. Dasatinib did not show significant adverse effects with clinical doses ex vivo but inhibited mGSC colony growth in vitro.
Interspecific interactions among major carnivores in Panna Tiger Reserve: A multispecies occupancy approach
Authors: Dutta Supratim , Maheswaran Gopinathan , Krishnamurthy Ramesh
Published: October 2024

Large carnivores play a crucial role in trophic cascades, affecting the population dynamics of both co‐predators and prey within an ecosystem. Understanding the significance of these carnivores in trophic interactions is essential for developing effective conservation and management strategies. We examined the effects of occupancy dynamics and patterns of species interactions and coexistence within the carnivore guild in the Panna Tiger Reserve in India. We collected camera trap data (two seasons, 2019) in a presence–absence framework and applied multispecies occupancy models to assess the occupancy, co‐occurrence, and interactions among species. We also examined activity overlap to understand the temporal segregation in the carnivore guild. The mean marginal occupancy was highest for leopards in winter (Ψwinter 0.92 ± 0.02, Ψsummer 0.63 ± 0.05) and hyenas in summer (Ψsummer 0.93 ± 0.03, Ψwinter 0.78 ± 0.03) and was lowest for tigers in both seasons (Ψwinter 0.62 ± 0.05, Ψsummer 0.15 ± 0.05). Co‐occurrence probability among carnivores was higher in winter than in summer, and conditional occupancy was consistently higher when other species were present. Different environmental factors influenced marginal occupancy and co‐occurrence patterns across seasons. Strong temporal overlaps were recorded between tiger–leopard (0.87–0.91) and tiger–hyena (0.78–0.79). We detected a significant spatial segregation between tigers and leopards, as they prefer different habitat types in different seasons, along with high temporal overlap. Resource availability strongly governs the association of carnivores with their habitat selection. Hyenas demonstrated higher dependency on tigers than on leopards for resources. These findings indicate that coexistence with apex‐predator species is feasible through strategic adaptation to fulfill resource requisition.
Mid‐term outcomes of valve replacement surgery with or without coronary artery bypass grafting in patients with overweight and obesity: A cohort study
Authors: Rajablou Nadia , Tashak Golroudbari Hasti , Ahmadi Tafti Seyed Hossein , Bagheri Jamshid , Zoroufian Arezou , Sahebjam Mohammad , Salehbeigi Shahrzad , Lesani Zohreh , Omidi Negar
Published: October 2024

Current data evaluating outcomes of valve replacement surgery in patients with overweight/obesity is contradictory. There is a scarce study comparing outcomes of valve surgery considering the type of valve involved in the procedure. We followed outcomes in patients with overweight and obesity after valve replacement surgery with or without coronary artery bypass graft (CABG) and also patients with aortic valve replacement (AVR) and mitral valve replacement (MVR), separately to compare their mid‐term prognosis in each group. Consecutive patients who had undergone cardiac valve surgery with or without CABG in Tehran Heart Center were enrolled. We enrolled 3158 patients. Median survival was 125.71 ± 82.20 weeks in patients with overweight/obesity. We found a significantly higher LVDd, LVDs and RVDd in patients with CABG (51.85 ± 7.31, 36.80 ± 8.81 and 30.04 ± 3.58, respectively) compared to the valve group (50.10 ± 6.35 mm, 35.08 ± 7.29 mm and 29.76 ± 4.07 mm, respectively). All‐cause mortality is significantly higher in patients with AVR (5.7%) than those with MVR (3.3%). Patients with CABG are at higher risk of myocardial infarction (MI) compared to the ones without CABG (0.8% vs. 0.1%). No significant interaction was observed between the type of valve surgery (AVR/MVR) or valve surgery combinations (valve/valve + CABG) (p‐values = .81 vs. .97, respectively). Post‐operative outcomes in patients with overweight/obesity depend on several factors such as type of valve involved and presence of CABG. Risk management can lower the rate of mortality and morbidity in these patients.
Delineating the neural substrates of autobiographical memory impairment in Huntington's disease
Authors: Horne Kristina , Carmichael Anna , Mercieca Emily‐Clare , Glikmann‐Johnston Yifat , Stout Julie C. , Irish Muireann
Published: October 2024

Emerging evidence suggests that autobiographical memory (ABM) is altered in Huntington's disease (HD). While these impairments are typically attributed to frontostriatal dysfunction, the neural substrates of ABM impairment in HD remain unexplored. To this end, we assessed ABM in 30 participants with genetically confirmed HD (18 premanifest, 12 manifest) and 24 age‐matched healthy controls. Participants completed the Autobiographical Interview to assess free and probed ABM recall and underwent structural brain imaging. Whole‐brain voxel‐based morphometry (VBM) was used to explore voxel‐wise associations between ABM performance and grey matter intensity (False Discovery Rate corrected at q = 0.05). Relative to controls, HD participants displayed significantly less detailed ABM retrieval across free and probed recall conditions, irrespective of disease stage. Recall performance did not differ significantly between manifest and premanifest HD groups. VBM analyses indicated that poorer ABM performance was associated with atrophy of a distributed cortico‐subcortical network. Key regions implicated irrespective of ABM condition included the bilateral occipital cortex, left precuneus, right parahippocampal gyrus and right caudate nucleus. In addition, probed ABM recall was associated with the superior and inferior frontal gyri, frontal pole, right hippocampus, nucleus accumbens, paracingulate gyrus and cerebellum. Overall, our findings indicate that ABM impairments in HD reflect the progressive degeneration of a distributed cortico‐subcortical brain network comprising medial temporal, frontal, striatal and posterior parietal cortices. Our findings advance our understanding of the neurocognitive profile of HD, providing an important foundation for future interventions to support memory function in this population.
Basic or applied research in university–industry collaborations? An analysis of research orientations in knowledge creation partnerships
Authors: Cabanes Benjamin , Plantec Quentin , Le Masson Pascal , Weil Benoît
Published: October 2024

In a knowledge‐based economy, university–industry collaborations play a pivotal role in driving innovation and economic growth. This study investigates the research orientations of these collaborations, focusing on the balance between basic and applied research. Using data from 631 collaborative projects funded by the French Cifre PhD programme, we find that most projects emphasize basic research (61%), contradicting the common expectation that industry‐led partnerships primarily focus on applied research. Importantly, our analysis reveals that this preference for basic research is not contingent on traditional contextual factors such as scientific discipline, company size or university type. These findings challenge established assumptions in the literature and suggest that even in industry‐sponsored research, fundamental inquiry is critical in supporting long‐term innovation strategies. This paper contributes to the understanding of research orientations in university–industry collaborations and offers practical suggestions for enhancing these partnerships and informing research policy. Additionally, we outline a research agenda for further exploration of the factors influencing research orientations, the impact of early‐stage industry engagement and the role of policies in shaping collaboration outcomes.
Implications of the non‐neuronal cholinergic system for therapeutic interventions of inflammatory skin diseases
Authors: Qu Hui‐Qi , Kao Charlly , Hakonarson Hakon
Published: October 2024

The pivotal roles of acetylcholine (ACh) in physiological processes encompass both the nervous and non‐neuronal cholinergic systems (NNCS). This review delineates the synthesis, release, receptor interactions, and degradation of ACh within the nervous system, and explores the NNCS in depth within skin cells including keratinocytes, endothelial cells, fibroblasts, macrophages, and other immune cells. We highlight the NNCS's essential functions in maintaining epidermal barrier integrity, promoting wound healing, regulating microcirculation, and modulating inflammatory responses. The potential of the NNCS as a therapeutic target for localized ACh regulation in the skin is discussed, though the translation of these findings into clinical practice remains uncertain due to the complexity of cholinergic signalling and the lack of comprehensive human studies. The review progresses to therapeutic modulation strategies of the NNCS, including AChE inhibitors, nicotinic and muscarinic receptor agonists and antagonists, choline uptake enhancers, and botulinum toxin, highlighting their relevance in dermatology. We highlight the impact of the NNCS on prevalent skin diseases such as psoriasis, atopic dermatitis, rosacea, acne, bullous diseases, hyperhidrosis and hypohidrosis, illustrating its significance in disease pathogenesis and therapy. This comprehensive overview aims to enhance understanding of the NNCS's role in skin health and disease, offering a foundation for future research and therapeutic innovation.
TROP2 Expression and Therapeutic Implications in Cutaneous Squamous Cell Carcinoma: Insights From Immunohistochemical and Functional Analysis
Authors: Tanegashima Keiko , Tanaka Yuka , Ito Takamichi , Oda Yoshinao , Nakahara Takeshi
Published: October 2024

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer, but treatments for advanced cases have limited efficacy. Trophoblast cell‐surface antigen 2 (TROP2) is a cell‐surface protein that is widely expressed in various tumours, where it exerts significant influence over critical processes such as tumour cell growth, apoptosis, migration, invasion and metastasis. Sacituzumab govitecan, an antibody‐drug conjugate (ADC) targeting TROP2, is emerging as a promising strategy for anticancer therapy. In this study, we investigated TROP2 expression in cSCC tissues from 51 patients and evaluated its function in the A431 human SCC cell line. Immunohistochemical analysis revealed TROP2 expression on the plasma membrane of cSCC tissues and A431 cells. A431 cells showed sensitivity to sacituzumab govitecan with a significant concentration‐dependent decrease in viable cell number. In addition, Knockdown of TROP2 resulted in decreased expression of cyclin D1 and BCL‐2, along with reduced cell viability. Knockdown of TROP2 also resulted in decreased expression of vimentin, along with reduced migratory capacity. These findings suggest that TROP2 plays a crucial role in cSCC cell proliferation and migration, and highlight the potential of sacituzumab govitecan as a promising therapeutic option for cSCC.
Treatment of a patient with inoperable tumoral calcinosis associated with end stage kidney disease: A case report
Authors: Couser Sarah K. , Claes Donna J. , Huesman Sydney , Hooper David K.
Published: October 2024

We describe a case of severe symptomatic tumoral calcinosis in a young man with end stage kidney disease secondary to antineutrophil cytoplasmic antibodies‐associated vasculitis with longstanding hyperphosphatemia and secondary hyperparathyroidism while on several years of peritoneal dialysis. The use of intravenous sodium thiosulfate, optimization of clearance with five times weekly hemodialysis, and intradialytic nutrition were used to treat his inoperable tumoral calcinosis. Over 3 months, he had a remarkable reduction in the size of his calcified masses and associated improvement in pain. He subsequently received a living donor kidney transplant.
The Experiences and Perceptions of Telehealth in Patients Living With Advanced Chronic Obstructive Pulmonary Disease: A Qualitative Evidence Synthesis
Authors: O'Connor Úna , Crilly Geraldine
Published: October 2024

Aim

To systematically identify, appraise and synthesise qualitative research evidence which examined the impact of telehealth on the experiences and perceptions of patients living with advanced chronic obstructive pulmonary disease, to inform the development of patient‐centred telehealth.

Design

Qualitative evidence synthesis.

Database Searches

CINAHL, Cochrane, Embase, PUBMED, MEDLINE, EThOS, Web of Science, PsycINFO, Lenus, DART, RIAN and ProQuest were searched for primary qualitative studies undertaken between 2008 and 2023.

Methods

A thematic synthesis of studies was undertaken to identify descriptive themes relating to patient views. Methodological quality was assessed using the Critical Appraisal Skills Programme framework, and confidence in review findings was assessed using the GRADE‐CERQual approach.

Findings

Nine studies met the inclusion criteria and were included in the final synthesis. Four analytical themes were generated (1) telehealth as a facilitator of independence, (2) the influence of patient and healthcare provider relationship on successful engagement with telehealth, (3) usability of telehealth to patients living with advanced chronic obstructive pulmonary disease and (4) trusting virtual health services and facilitating confidence in the patient/service user. Five descriptive themes emerged: (i) individualised telehealth chronic obstructive pulmonary disease care (ownership and control), (ii) managing chronic obstructive pulmonary disease exacerbations, (iii) being heard and feeling understood, (iv) telehealth as an education aid and (v) aging and virtual technology.

Conclusion

Understanding the experiences of patients with chronic obstructive pulmonary disease and their engagement with telehealth is a necessary determinant of how best to utilise telehealth in this population and may serve to inform policymakers to further develop and implement telehealth into practice. Future research on patients and healthcare professionals' views on telehealth use in the palliative stage of this illness may also be valuable.

Impact

Findings add value by providing healthcare providers with additional evidence to improve understanding of both telehealth complexity and human experiences and perceptions. It is anticipated that a deeper understanding of chronic obstructive pulmonary disease patients' experiences and perceptions will inform the development of strategies to maximise and enhance the application of patient‐centred telehealth within the context of coping and living with a debilitating condition.

Patient or Public Contribution

No patient or public contribution was utilised in this study.
The role of different types of knowledge and expertise in explaining recognition justice in flood defence and flood risk prevention
Authors: Paauw Mandy , Crabbé Ann , Guevara Viquez Sofia , Priest Sally
Published: October 2024

Flood risks worldwide are rising and it is increasingly recognised that the impacts of floods are not neutral. Socioeconomic and demographic characteristics determine people's capacity to deal with flood events. These differences in social vulnerability to floods need to be considered in flood risk management (FRM) to prevent the most vulnerable groups from being disproportionately impacted. However, due to a diversification of FRM strategies and the involvement of various policy domains, the experts working on FRM are no longer a homogeneous group. Where FRM was previously dominated by engineers, now various experts are involved that have different disciplinary backgrounds, knowledge bases and approaches to FRM. As a result, they also differ in their recognition of social vulnerability to floods. In this paper, we explore the different types of knowledge and expertise in FRM in three countries (England, Flanders and France), focussing on the strategies of flood defence and flood risk prevention. We characterise the epistemic communities supporting the domains and study to what extent experts differ in their recognition of social vulnerability to floods. We also dive into the mechanisms employed to stimulate integration between experts and consider the extent to which this integration can strengthen recognition justice.
Mental workload as a predictor of burnout in intensive care nurses
Authors: Gündüz Emine Selda , Öztürk Nilgün Kavrut
Published: October 2024

Background

Nurses face a high level of mental workload while performing their duties. High levels of mental workload can negatively impact nurses.

Aim

The aim of this research was to determine the relationship between mental workload and burnout levels of intensive care nurses.

Study design

Descriptive‐correlational design has been adopted in this research. The sample consisted of 156 nurses working in the intensive care units of a hospital in the south of Turkey between September and December 2023. Research data were collected with the ‘Participant Information Form’, which includes socio‐demographic characteristics, ‘Mental Workload Scale’ and ‘Maslach Burnout Scale’.

Results

Almost all (95.5%) of the nurses participating in the study reported that their mental workload was high. It has been determined that there is a strong positive relationship between mental workload and burnout. According to the regression model obtained from the research, being a woman (β = .165, p = .008) and emotional workload (β = −695, p < .001) are determinants of emotional exhaustion. These variables explain emotional exhaustion at a rate of 50.1% (adjusted R2 = .501). Emotional workload (β = .399, p = .003) is the most important determinant of personal accomplishment. This variable explains 19.0% (adjusted R2 = .190) of personal accomplishment. The most important determinant of depersonalization is emotional workload (β = .324, p < .001). It was determined that this variable explained 24.4% (adjusted R2 = .244) of depersonalization.

Conclusions

This research revealed that there is a strong positive relationship between mental workload and burnout and that increasing mental workload can increase burnout.

Relevance to Clinical Practice

Nurses' risk of emotional exhaustion increases as mental workload increases. Reducing cognitive workload, temporary workload and emotional workload increases the personal accomplishment experienced by nurses. In addition, as temporary workload, emotional workload and performance‐related workload increase, the depersonalization experienced by nurses also increases.
Revealing hidden viruses inducing similar yellowing symptoms or remaining asymptomatic in cucurbit crops
Authors: de Moya‐Ruiz Celia , Juárez Miguel , Gómez Pedro
Published: October 2024

Mixed viral infections occur frequently in plants, leading to diseases that can be difficult to diagnose, especially when an unknown virus is hidden behind expression of symptoms common to other viruses. We monitored aphid‐ and whitefly‐transmitted viruses in two cucurbit crops (melon and watermelon) for three consecutive seasons (2021–2023) across three production regions in Spain, focusing on the common yellowing and mosaic symptoms. A total of 984 symptomatic leaf samples from 246 field plots were tested for 10 frequently found cucurbit viruses. Cucurbit aphid‐borne yellows virus (CABYV) was the most prevalent virus infecting both cucurbit crops over the three seasons. Additionally, occurrence of watermelon mosaic virus (WMV) in samples with mosaic symptoms was significant. However, an important proportion of yellowing symptomatic samples tested negative for known viruses. Using a sequence‐independent approach, we identified a novel polerovirus, Pepo aphid‐borne yellows virus (PABYV), which was widespread, infecting both crops. Analysis of our long‐term cucurbit frozen‐sample collection revealed that PABYV had emerged in Spain in 2018, possibly unnoticed as its yellowing symptoms were similar to CABYV, with which it was frequently associated. Additionally, we found the cryptic Cucumis melo endornavirus (CmEV) in all tested melon samples from 2011 and, for the first time, in pumpkin. Genetic characterization of CABYV, PABYV and CmEV populations revealed a replacement of ancient CABYV isolates by contemporary ones, while PABYV and CmEV isolates were genetically homogenous among their populations. This study underlines the need for continuous surveillance and further investigation into common symptoms of mixed viral infections.
Respublica Noumenon: Kant, Rousseau, and Plato's Republic
Authors: Kryluk Michael
Published: October 2024

This article examines the philosophical sources for Kant's interpretation of Plato's Republic and its impact on his conception of the ideal state. I argue that Kant's knowledge of Plato was not derived from Plato's writings, but from secondary accounts. More specifically, I focus on four authors whose discussions of Plato influenced Kant's understanding of the perfect republic: Brucker, Cicero, Wolff, and Rousseau. Two main claims emerge. First, I show that Kant's appeal to the Republic intervenes in a longstanding debate about the irrational and “enthusiastic” character of Platonic idealism. Second, I emphasize Rousseau's role in instigating Kant's interest in Plato and shaping his conception of the perfect, fully self‐legislating republic that serves as the regulative norm of the state which existing regimes can and should strive to emulate. The result of my analysis is a better understanding of Kant's relationship to Plato and Rousseau, as well as the philosophical motivations behind his version of the ideal republic.
A Multi-Scale Thermal-Mechanical Numerical Method for Mini-Channel Heat Exchanger Subjected to Fluid Pressure Loads
Authors: Xu Zirui , Zhang Xiaoxu , Tan Yin , Bi Jiyuan , Li Ri , Yang Xiongwei , Wang Qiuwang , Ma Ting
Published: October 2024

This study proposes a novel multi-scale numerical method for thermal-mechanical analysis of mini-channel heat exchangers (MCHEs) under internal fluid pressure and temperature loads. The method comprises a macro-scale model for global analysis and a meso-scale model for detailed submodel analysis, specifically focusing on the internal fluid pressure effects within the MCHEs. The macroscopic model divides the MCHE into cover plate and homogenized regions subjected to pressure and temperature loads. To incorporate internal pressures into the homogenized MCHE model, mathematical equations are formulated to convert internal fluid pressures into equivalent strain loads. Additionally, a novel equivalent thermal expansion method is introduced, integrating internal fluid pressure loads by prescribing equivalent thermal expansion coefficients alongside spatially-varying nodal temperature fields within the MCHE. The meso-scale models with detailed channel patterns are assigned to specific portions of the homogenized region. The integration of the mesoscale model into the macroscopic framework is achieved through the application of the submodel method. Comparisons between the equivalent and actual MCHE models show that the proposed equivalent method can provide accurate predictions for thermal-mechanical deformations and stresses, and significantly reduce the computational expenses.
Study on Dynamic Postbuckling Stability of Fast Reactor Vessels Subjected to Vertical Vibration
Authors: Ye Yiji , Ichimiya Masakazu , Kasahara Naoto
Published: October 2024

As a lesson learned from the Fukushima nuclear accident, the importance of accident mitigation for beyond-design basis events (BDBEs) is recognized. Excessive earthquake is a typical BDBE. During such events, the fast reactor vessel (FRV) is vulnerable to buckling. The safety goal of FRV under excessive earthquake is to achieve a stable post-buckling state. Our previous study on bending buckling confirmed a global response stability under horizontal vibration. As a parallel study, this paper focuses on axial compression buckling under vertical vibration. Shaking table experiments using thin-walled cylindrical models (R/t = 260) are carried out. Similar methodology is applied to investigate the buckling and post-buckling behavior. It is found that axial compression buckling shares an extensive similarity with bending buckling in both buckling mode and post-buckling behavior. Similar global response stability is confirmed due to phase-inverse phenomenon. After buckling, buckling failure becomes stable and does not progress further even when an intense input amplitude is continuously applied. The vibrational load acts as a displacement-controlled load in the out-of-phase domain such that immediate collapse is prevented. Most input energy is dissipated in hysteresis loops rather than being carried by the mass. These mechanisms are independent of input waveform and can be applied to an arbitrary seismic input. In addition, a conservative limit displacement for global response stability is identified. Moreover, the effect of the input frequency ratio, the initial geometrical imperfection, and the gravitational force on the post-buckling behavior are clarified.
Practical limits to spatial resolution of magnetic imaging with a quantum diamond microscope
Authors: Rietwyk Kevin J. , Shaji Alex , Robertson Islay O. , Healey Alexander J. , Singh Priya , Scholten Sam C. , Reineck Philipp , Broadway David A. , Tetienne Jean-Philippe
Published: October 2024

Widefield quantum diamond microscopy is a powerful technique for imaging magnetic fields with high sensitivity and spatial resolution. However, current methods to approach the ultimate spatial resolution (<500 nm) are impractical for routine use as they require time-consuming fabrication or transfer techniques to precisely interface the diamond sensor with the sample to be imaged. To address this challenge, we have designed a co-axial sensor holder that enables simple, repeatable sensor–sample interfacing while being compatible with high numerical aperture (NA) optics. With our new design we demonstrate low standoffs <500 nm with a millimeter sized sensor. We also explore the relationship between spatial resolution and NA spanning from 0.13 to 1.3. The spatial resolution shows good agreement with the optical diffraction limit at low NA but deviates at high NA, which is shown to be due to optical aberrations. Future improvements to our design are discussed, which should enable magnetic imaging with <500 nm resolution in an accessible, easy-to-use instrument.
Lineage tracing of stem cell–derived dopamine grafts in a Parkinson’s model reveals shared origin of all graft-derived cells
Authors: Storm Petter , Zhang Yu , Nilsson Fredrik , Fiorenzano Alessandro , Krausse Niklas , Åkerblom Malin , Davidsson Marcus , Yuan Joan , Kirkeby Agnete , Björklund Tomas , Parmar Malin
Published: October 2024

Stem cell therapies for Parkinson’s disease are at an exciting time of development, and several clinical trials have recently been initiated. Human pluripotent stem cells are differentiated into transplantable dopamine (DA) progenitors which are proliferative at the time of grafting and undergo terminal differentiation and maturation in vivo. While the progenitors are homogeneous at the time of transplantation, they give rise to heterogeneous grafts composed not only of therapeutic DA neurons but also of other mature cell types. The mechanisms for graft diversification are unclear. We used single-nucleus RNA-seq and ATAC-seq to profile DA progenitors before transplantation combined with molecular barcode-based tracing to determine origin and shared lineages of the mature cell types in the grafts. Our data demonstrate that astrocytes, vascular leptomeningeal cells, and DA neurons are the main component of the DAergic grafts, originating from a common progenitor that is tripotent at the time of transplantation.
Permeable void-free interface for all-solid-state alkali-ion polymer batteries
Authors: Lyu Wang , Fu Hongwei , Rao Apparao M. , Lu Zhiyu , Yu Xinzhi , Lin Yue , Zhou Jiang , Lu Bingan
Published: October 2024

All-solid-state batteries suffer from a loss of contact between the electrode and electrolyte particles, leading to poor cyclability. Here, a void-free ion-permeable interface between the solid-state polymer electrolyte and electrode is constructed in situ during cycling using charge/discharge voltage as the stimulus. During the charge-discharge, the permeation phase fills the voids at the interface and penetrates the electrode, forming strong bonds with the cathode and effectively mitigating the contact problem. Our all-solid-state potassium ion polymer batteries maintain high Coulombic efficiency more than 2000 cycles at a high operating voltage of 4.5 volt and stably cycle more than 500 cycles even at 4.6 volt. Our rational design for mitigating the contact problem is versatile, as demonstrated by the scalability of all-solid-state graphite-based polymer potassium-ion pouch cells and all-solid-state lithium-ion polymer batteries.
Programmable bacteria synergize with PD-1 blockade to overcome cancer cell–intrinsic immune resistance mechanisms
Authors: Li Fangda , Yang Zaofeng , Savage Thomas M. , Vincent Rosa L. , de los Santos-Alexis Kenia , Ahn Alexander , Rouanne Mathieu , Mariuzza Dylan L. , Danino Tal , Arpaia Nicholas
Published: October 2024

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3
−
CD4
+
and CD8
+
T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.
Layer segmented filamentous bacteria colonize and impact gut health of broiler chickens
Authors: Meinen-Jochum Jared , Skow Caleb J. , Mellata Melha
Published: October 2024

In commercial poultry farms, chicks hatch away from their progenitors from which they acquire key host-specific microbiota, like segmented filamentous bacteria (SFB) involved in gut maturation in early life. This study investigated whether providing chicken SFB to newly hatched broilers would increase their gut maturation and resistance to bacteria relevant to broiler and human health. One-day-old Ross308 broilers were orally treated with either phosphate-buffered saline (CON) or layer-derived SFB (D-SFB). On days 5, 10, 17, and 24, feces were collected to detect and enumerate SFB and
Enterobacteriaceae
. On days 8, 15, 22, and 29, birds were euthanized, intestinal samples were collected to detect and enumerate SFB through quantitative PCR (qPCR) and microscopy and expression of genes associated with gut immune function through reverse transcription-qPCR. This study showed that, despite their host specificity, layer SFB can colonize their genetically distinct relative broilers. Ileal SFB colonization was accelerated by a week with the SFB treatment and covered the proximal, medial, and distal sections of the ileum. Colonization of the ileum by SFB in early life highly activated gene expression of intestinal barrier proteins and cytokines, e.g., IL-10 and IFNγ but not IL-17. SFB treatment reduced the level of
Enterobacteriaceae
in the gut and provided superior resistance to intestinal and extraintestinal pathogens as tested
in vitro
. Overall, early gut colonization of SFB is imperative for the maturation of the gut immune system and the establishment of a homeostatic gut environment. Improving our understanding of gut immune maturation in food-producing animals is crucial for both human and animal health.

IMPORTANCE

In commercial farms, newly hatched chicks may lack host-specific microbiota that help mature their gut immune system for lifelong health benefits. Here, introducing an avian segmented filamentous bacteria (SFB) to commercially sourced chickens orally at hatch accelerated SFB colonization of the ileum. Remarkably, SFB from layers were able to colonize broilers and enhance gut immune maturation, and this immunomodulation impacted the ability to increase intestinal and extraintestinal resistance to bacteria relevant to poultry and human health. With the antibiotic restrictions in animal production, strategies that will help mitigate infections are urgently needed. In summary, we developed a live prophylactic for newly hatched chicks to improve animal health and food safety. Due to the host specificity of SFB, our data highlight the importance of investigating the molecular mechanism of SFB interaction in their own host.
E.PathDash, pathway activation analysis of publicly available pathogen gene expression data
Authors: Taub Lily , Hampton Thomas H. , Sarkar Sharanya , Doing Georgia , Neff Samuel L. , Finger Carson E. , Ferreira Fukutani Kiyoshi , Stanton Bruce A.
Published: October 2024

E.PathDash facilitates re-analysis of gene expression data from pathogens clinically relevant to chronic respiratory diseases, including a total of 48 studies, 548 samples, and 404 unique treatment comparisons. The application enables users to assess broad biological stress responses at the KEGG pathway or gene ontology level and also provides data for individual genes. E.PathDash reduces the time required to gain access to data from multiple hours per data set to seconds. Users can download high-quality images such as volcano plots and boxplots, differential gene expression results, and raw count data, making it fully interoperable with other tools. Importantly, users can rapidly toggle between experimental comparisons and different studies of the same phenomenon, enabling them to judge the extent to which observed responses are reproducible. As a proof of principle, we invited two cystic fibrosis scientists to use the application to explore scientific questions relevant to their specific research areas. Reassuringly, pathway activation analysis recapitulated results reported in original publications, but it also yielded new insights into pathogen responses to changes in their environments, validating the utility of the application. All software and data are freely accessible, and the application is available at
scangeo.dartmouth.edu/EPathDash
.

IMPORTANCE

Chronic respiratory illnesses impose a high disease burden on our communities and people with respiratory diseases are susceptible to robust bacterial infections from pathogens, including
Pseudomonas aeruginosa
and
Staphylococcus aureus
, that contribute to morbidity and mortality. Public gene expression datasets generated from these and other pathogens are abundantly available and an important resource for synthesizing existing pathogenic research, leading to interventions that improve patient outcomes. However, it can take many hours or weeks to render publicly available datasets usable; significant time and skills are needed to clean, standardize, and apply reproducible and robust bioinformatic pipelines to the data. Through collaboration with two microbiologists, we have shown that E.PathDash addresses this problem, enabling them to elucidate pathogen responses to a variety of over 400 experimental conditions and generate mechanistic hypotheses for cell-level behavior in response to disease-relevant exposures, all in a fraction of the time.
Depletion of m
6
A-RNA in
Escherichia coli
reduces the infectious potential of T5 bacteriophage
Authors: Saikia Bibakhya , Riquelme-Barrios Sebastian , Carell Thomas , Brameyer Sophie , Jung Kirsten
Published: October 2024

N
6
-Methyladenosine (m
6
A) is the most abundant internal modification of mRNA in eukaryotes that plays, among other mechanisms, an essential role in virus replication. However, the understanding of m
6
A-RNA modification in prokaryotes, especially in relation to phage replication, is limited. To address this knowledge gap, we investigated the effects of m
6
A-RNA modifications on phage replication in two model organisms:
Vibrio campbellii
BAA-1116 (previously
Vibrio harveyi
BB120) and
Escherichia coli
MG1655. An m
6
A-RNA-depleted
V. campbellii
mutant (Δ
rlmF
Δ
rlmJ
) did not differ from the wild type in the induction of lysogenic phages or in susceptibility to the lytic Virtus phage. In contrast, the infection potential of the T5 phage, but not that of other T phages or the lambda phage, was reduced in an m
6
A-RNA-depleted
E. coli
mutant (Δ
rlmF
Δ
rlmJ
) compared to the wild type. This was shown by a lower plaquing efficiency and a higher percentage of surviving cells. There were no differences in the T5 phage adsorption rate, but the mutant exhibited a 5-min delay in the rise period during the one-step growth curve. This is the first report demonstrating that
E. coli
cells with lower m
6
A-RNA levels have a higher chance of surviving T5 phage infection.

IMPORTANCE

The importance of RNA modifications has been thoroughly studied in the context of eukaryotic viral infections. However, their role in bacterial hosts during phage infections is largely unexplored. Our research delves into this gap by investigating the effect of host
N
6
-methyladenosine (m
6
A)-RNA modifications during phage infection. We found that an
Escherichia coli
mutant depleted of m
6
A-RNA is less susceptible to T5 infection than the wild type. This finding emphasizes the need to further investigate how RNA modifications affect the fine-tuned regulation of individual bacterial survival in the presence of phages to ensure population survival.
Emerging
bla
NDM
-positive
Salmonella enterica
in Chinese pediatric infections
Authors: Ke Yefang , Zhu Zhe , Lu Wenbo , Liu Wenyuan , Ye Lina , Jia Chenghao , Yue Min
Published: October 2024

Non-typhoidal
Salmonella
(NTS) is a common zoonotic foodborne pathogen, whose rising antimicrobial resistance has been an urgent threat to global public health. Here, we reported two carbapenem-resistant
Salmonella enterica
(CRSE) strains (NBFE-049 and NBFE-164) carrying the
bla
NDM
genes, which were recovered from two Chinese children, belonged to
Salmonella enterica
serovar Typhimurium (
S
. Typhimurium) monophasic variant (
S
. 1,4,[5],12:i:-) ST34 (a sequence type) and
S
. Typhimurium ST19, respectively. Genes
bla
NDM-5
and
bla
NDM-13
were detected in NBFE-049 and NBFE-164, respectively. The
bla
NDM-5
in NBFE-049 was located in an IncHI2-type plasmid, named pNBFE-049. In NBFE-164, the
bla
NDM-13
was located in an IncI1-type plasmid, named pNBFE-164. The plasmid pNBFE-164 successfully transferred its resistance phenotype into the recipient strain
Escherichia coli
J53 with a high efficiency of 1.1 × 10
−2
, while no transconjugants were obtained in pNBFE-049 conjugation assays. We further elucidated the genetic relationships of globally occurring New Delhi Metallo-β-lactamase (NDM)-positive strains and locally distributed clinical strains within the same serovar. The closest relative of NBFE-049 was clinical
Salmonella
strain 1722, which was recovered in 2020 and differed by only three Single Nucleotide Polymorphisms (SNPs). No NDM-positive ST19 could be found in the National Center for Biotechnology Information (NCBI) database, and NBFE-164 showed a close genetic relationship with the other ST19 in this area. To sum up, we suggested the potential contributions of clonal spread and plasmid-mediated
bla
NDM
transfer in CRSE dissemination. This study reported the complete genome of two
bla
NDM
-carrying
S
. Typhimurium isolates, shedding new insights into the antimicrobial resistance mechanisms and dissemination patterns of the emerging CRSE.

IMPORTANCE

NTS is one of the most common zoonotic pathogens that causes foodborne illnesses, while
S
. Typhimurium is one of the most common serovars. With the rising prevalence of multi-resistant
Salmonella
worldwide, carbapenems have emerged as the last-line antibiotics for treating severe bacterial infections. In this study, we reported the genomic characteristics of two carbapenem-resistant
S
. Typhimurium strains, which were recovered from two pediatric patients, carrying
bla
NDM-5
and
bla
NDM-13
, providing new insights into the antimicrobial resistance deteriminants and transmission risk of
bla
NDM
-positive NTS in China. We suggested the potential contributions of clonal spread and plasmid-mediated
bla
NDM
transfer in CRSE dissemination. Future enhanced surveillance policy should mitigate CRSE spreading, and more importantly, clinical antimicrobial therapeutic regimens should be adjusted accordingly.
Development of a new
Acinetobacter baumannii
pneumonia rabbit model for the preclinical evaluation of future anti-infective strategies
Authors: Albac S. , Anzala N. , Bonnot D. , Djama C. , Chavanet P. , Croisier D.
Published: October 2024

Carbapenem-resistant
Acinetobacter baumannii
(CRAB) is an emerging cause of hospital-acquired pneumonia (HAP). Preclinical large models are warranted to predict the efficacy and the resistance profile of anti-infectives and mimic how they will be used in the human treatment of CRAB-HAP. Here we reported on the development of an
Acinetobacter baumannii
experimental pneumonia model in immunocompromised rabbits, receiving a 48-h human-simulated regimen. The efficacy of meropenem (2 g/q8h i.v. over prolonged 3-h perfusion), rifampin (25 mg/kg/q8h, i.v.), or the combination of meropenem and rifampin was assessed in rabbits infected with the carbapenem-susceptible
ATCC 17978
reference strain or the CRAB
Turc 2
clinical strain. The emergence of rifampin mutants was also investigated. Meropenem demonstrated a strong pulmonary bacterial reduction in animals infected with the
ATCC 17978
strain (unlike the CRAB strain). The high rifampin dosage was associated with a 1.3 Log
10
bacterial killing on average but induced the emergence of high-level resistant mutants in 80%–100% of animals, depending on the strain. The adjunction of rifampin to meropenem did not improve the bioburden in the lungs but partially reduced the number of animals exhibiting resistant mutants, whatever the tested strain. However, this adjunctive treatment was insufficient to overcome the emergence of resistance since mutation prevention concentration-related pharmacodynamic indices were unattainable at this dose. This CRAB pneumonia rabbit model represents an innovative tool to evaluate the efficacy of new or existing therapies and will provide informative data on how they can meet the resistance pharmacodynamic targets, which now need to be investigated before deciding on clinical therapeutic regimens.

IMPORTANCE

Within intensive care unit settings, carbapenem-resistant
Acinetobacter baumannii
(CRAB) has emerged as a frequent cause of hospital-acquired pneumonia (HAP) with poor clinical outcomes. This multidrug-resistant pathogen remains very challenging to study in clinical trials, and the U.S. Food and Drug Administration highlighted the limitations of existing small animal models for evaluating antibacterial or prophylactic strategies against such critical infections. These limitations include the difficulty in anticipating the risk of the emergence of resistance during treatment. Here we developed a new
Acinetobacter baumannii
pneumonia rabbit model using high inoculum. We demonstrated the emergence of resistance with rifampin, an existing antibiotic debated as a rescuing option to treat CRAB infections; and even intensified rifampin doses failed to close the mutant selection window. This CRAB pneumonia rabbit model represents a valuable tool to evaluate the efficacy of new or existing therapies and provides supportive data in antimicrobial resistance pharmacodynamics.