bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabrication and characterization of a hydrocolloid wound dressing functionalized with human placental derived extracellular matrix for management of skin wounds: An animal study
Authors: Jafari Davod , Gholipourmalekabadi Mazaher , Alizadeh Sanaz , Rajabi Fomeshi Motahareh , Amoupour Moein , Samadikuchaksaraei Ali
Published: November 2023

Background

Functionalization of wound dressing is one of the main approaches for promoting wound healing in skin wound management. In this study, our aim is to fabricate a bio‐functionalized hydrocolloid wound dressing.

Methods

The extracellular matrix (ECM) was extracted from human placental tissue. A hydrocolloid film was fabricated using Na‐CMC, pectin, gelatin, styrene‐isoprene‐styrene adhesive, glycerol, and 0.5%–2.5% powdered ECM. A polyurethane film and a release liner were used in the hydrocolloid/ECM films. The mechanical, adhesion, swelling rate, and integrity of the films were investigated. Cell proliferation, adhesion, and migration assays, as well as, SEM and FTIR spectroscopy were also conducted. Macroscopic and microscopic evaluations of wound healing process and formation of blood vessels were conducted in mouse animal models.

Results

We successfully fabricated a three‐layered ECM‐functionalized hydrocolloid dressing with a water vapor transmission rate of 371 g/m2/day and an adhesion peel strength of 176 KPa. Cellular adhesion, proliferation and migration were promoted by ECM. In the animal tests, ECM‐functionalized hydrocolloids significantly improved wound closure and re‐epithelialization at days 14 and 21. Also, ECM‐functionalized hydrocolloids promoted the formation of hair follicles.

Conclusions

Our findings suggest that ECM could enhance the wound healing properties of hydrocolloid wound dressings. This wound dressing could be considered for application in hard‐to‐heal acute wounds.
Effect of oral clonidine on pain reduction in patients with opioid use disorder in the emergency department: A randomized clinical trial
Authors: Rostamipoor Zahra , Nazemi‐Rafi Masoomeh , Mirafzal Amirhossein , Ilka Shahab , Hosseininasab Masumeh
Published: November 2023

Aims

Pain can create physical and psychosocial discomfort. Pain management of patients with opioid misuse history can be challenging, in part due to their tolerance to opioids. Clonidine is an alpha‐2 agonist that has been used for the reduction of anxiety and pain. The aim of this study was to investigate the effect of oral clonidine on pain outcomes in patients with a history of opioid use disorder presenting with orthopaedic fractures in the emergency room.

Methods

In this blinded clinical trial in the emergency department, 70 opioid‐dependent patients with orthopaedic fractures were divided into a control group of 35 and an intervention group of 35 subjects. Initially, 0.2 mg of oral clonidine was given to the intervention group and the control group received placebo tablets. Pain levels were recorded based on the Numerical Rating Scale rating before intervention, at 30 min, 1 h after intervention and at disposition from the emergency room (3‐6 h after intervention). The total morphine requirement was also recorded.

Results

The pain score of the clonidine group was significantly lower than that of the control group at 1 h and at disposition time. The amount of morphine required was significantly reduced in the clonidine group (P < 0.05). Oral clonidine had no significant effect on pulse rate. Oral clonidine was more effective for pain reduction in lower limb injuries.

Conclusion

Oral clonidine significantly reduced pain and the need for morphine in opioid‐dependent patients with orthopaedic fractures.
Paclitaxel may inhibit migration and invasion of gastric cancer cells via nod‐like receptor family pyrin domain‐containing 3/caspase‐1/Gasdermin E mediated pyroptosis pathway
Authors: Xu Peng‐peng , Wu Jie , Zhang Jing , Yu Tian‐yue , Wang Yu‐bin
Published: November 2023

Gastric cancer (GC) is a gastric epithelium‐derived malignancy insensitive to post‐surgical radiotherapy. Paclitaxel, an anti‐microtubule drug, has been proven to induce apoptosis of GC cells; however, its exact mechanism of action is unclear. Therefore, the molecular mechanism by which paclitaxel inhibits the proliferation, migration and invasion of GC cells was investigated in this study. First off, SNU‐719 cells were co‐cultured with paclitaxel and/or Caspase1 inhibitor VX765. Then the proliferation ability of the cells was detected by MTT after paclitaxel treatment (0, 10, 20, 40, and 80 nM), the migration ability by scratch assay, and the invasion ability by Transwell assay. Next, the levels of interleukin (IL)‐1β and IL‐18 in cell culture supernatant were detected by the enzyme linked immunosorbent assay (ELISA). And the level of lactate dehydrogenase (LDH) in the supernatant was measured by a corresponding kit. Finally, western blot was performed to detect the concentrations of Gasdermin E (GSDME), GSDME‐N, nod‐like receptor family pyrin domain‐containing 3 (NLRP3), caspase‐1, cleaved caspase‐1 protein in GC cells. As a result, paclitaxel inhibited the proliferation, migration, and invasion of SNU‐719 cells in a concentration‐dependent manner. Moreover, it induced the pyroptosis of SNU‐719 cells. After cell co‐culture with VX765 paclitaxel showed decreased inhibitory effect on the migration and invasion of SNU‐719 cells. VX765, additionally, suppressed the NLRP3/caspase‐1/GSDME mediated pyroptosis pathway activated by paclitaxel. In a nutshell, paclitaxel may inhibit the migration and invasion of GC cells SNU‐719 through the NLRP3/caspase‐1/GSDME mediated pyroptosis pathway.
Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma
Authors: Chung Hye Yoon , Shin Ha Young , Choi Young‐Chul , Park Hyung Jun , Lee Jin Gu , Lee Chang Young , Park Byung Jo , Kim Gi Jeong , Kim Seung Woo
Published: November 2023

Background and purpose

Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma‐associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG.

Methods

We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC‐positive and GC‐negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed.

Results

Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC‐positive, whereas 175 were GC‐negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC‐positive group than in the GC‐negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358–105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029–0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742–67.000) were significantly associated with postthymectomy MG.

Conclusions

Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.
Harnessing mobility data to capture changing work from home behaviours between censuses
Authors: Gibbs Hamish , Ballantyne Patrick , Cheshire James , Singleton Alex , Green Mark A.
Published: November 2023

This paper provides an analysis of working from home patterns in England using data from the 2021 Census to understand (1) how patterns of working from home (WFH) in England have shifted since the COVID‐19 pandemic and (2) whether human mobility indicators, specifically Google Community Mobility Reports, provide a reliable proxy for WFH patterns recorded by the 2021 Census, providing a formal evaluation of the reliability of such datasets, whose applications have grown exponentially over the COVID‐19 pandemic. We find that WFH patterns recorded by the 2021 Census were unique compared with previous UK censuses, reflecting an unprecedented increase likely caused by persistent changes to employment during the COVID‐19 pandemic, with a clear social gradient emerging across the country. We also find that Google mobility in ‘Residential’ and ‘Workplace’ settings provides a reliable measurement of the distribution of WFH populations across Local Authorities, with varying uncertainties for mobility indicators collected in different settings. These findings provide insights into the utility of such datasets to support population research in intercensal periods, where shifts may be occurring, but can be difficult to quantify empirically.
T‐cell receptor repertoire analysis of CD4‐positive T cells from blood and an affected organ in an autoimmune mouse model
Authors: Ishikawa Tatsuya , Horie Kenta , Takakura Yuki , Ohki Houko , Maruyama Yuya , Hayama Mio , Miyauchi Maki , Miyao Takahisa , Hagiwara Naho , Kobayashi Tetsuya J. , Akiyama Nobuko , Akiyama Taishin
Published: November 2023

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study aimed to investigate the correlation of TCRα and β repertoires in blood T cells with the extent of autoimmune signs that varies among individuals. We sequenced TCRα and β of CD4+CD44highCD62Llow T cells in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy. Data analysis revealed that the degree of similarity in TCR sequences between the blood and stomach varied among individual AIRE KO mice and reflected the extent of T cell infiltration in the stomach. We identified a set of TCR sequences whose frequencies in blood might correlate with extent of the stomach manifestations. Our results propose a potential of using TCR repertoires not only for diagnosing disease development but also for diagnosing affected organs in autoimmune diseases.
Perspectives of women living with type 1 diabetes regarding preconception and antenatal care: A qualitative evidence synthesis
Authors: Toledo‐Chavarri Ana , Delgado Janet , Rodríguez‐Martín Beatriz
Published: November 2023

Introduction

Pregnant women with type 1 diabetes may have an increased risk of complications for both the baby and themselves. Educational programmes, preconception planning, strict glycemic control and comprehensive medical care are some of the antenatal interventions that have been proposed to improve the outcomes of pregnant women with type 1 diabetes. While some evidence‐based recommendations about antenatal care are included in clinical practice guidelines (CPGs), the views, and experiences of women with type 1 diabetes about these interventions are not well known.

Aim

To understand and synthesize the perceptions of women with type 1 diabetes about the interventions before pregnancy.

Method

A qualitative evidence synthesis (QES) was carried out with a framework analysis guided by the Cochrane Qualitative and Implementation Methods Group approach. Three online databases (Medline, Embase and Web of Science) were searched. We included qualitative articles that were published from 2011 to 2021 and which were available in English or Spanish.

Findings

Ten references met the inclusion criteria of the study and were included. Three main themes were identified: (a) acceptability of antenatal care, (b) feasibility and implementation consideration and (c) equity and accessibility difficulties.

Conclusion

Continuity of care, coordination between health professionals and services, and a more holistic approach are the key aspects women say need to be considered for more acceptable, feasible and equitable preconception and antenatal care.

Patient or Public Contribution

This QES was carried out as part of the CPGs on diabetes mellitus type 1, carried out as part of the Spanish Network of Health Technology Assessment Agencies. In this CPG, the representatives of the patient associations are Francisco Javier Darias Yanes, from the Association for Diabetes of Tenerife, who has participated in all the phases of the CPG; Aureliano Ruiz Salmón and Julián Antonio González Hernández (representatives of the Spanish Diabetes Federation (FEDE) who have participated as collaborator and external reviewer, respectively.
Risk factors for sternal wound infection after open‐heart operations: A systematic review and meta‐analysis
Authors: Chen Dongsheng , Zhang Jianghe , Wang Yuting , Jiang Weiqian , Xu Yujian , Xiong Chenlu , Feng Zekun , Han Yan , Chen Youbai
Published: November 2023

We aimed to quantitatively and systematically elucidate the rationality of the examined variables as independent risk factors for sternal wound infection. We searched databases to screen studies, ascertained the variables to be analysed, extracted the data and applied meta‐analysis to each qualified variable. Odds ratios and mean differences were considered to be the effect sizes for binary and continuous variables, respectively. A random‐effects model was used for these procedures. The source of heterogeneity was evaluated using a meta‐regression. Publication bias was tested by funnel plot and Egger's test, the significant results of which were then calculated using trim and fill analysis. We used a sensitivity analysis and bubble chart to describe their robustness. After screening all variables in the eligible literature, we excluded 55 because only one or no research found them significant after multivariate analysis, leaving 33 variables for synthesis. Two binary variables (age over 65 years, NYHA class >2) and a continuous variable (preoperative stay) were not significant after the meta‐analysis. The most robust independent risk factors in our study were diabetes mellitus, obesity, use of bilateral internal thoracic arteries, chronic obstructive pulmonary disease, prolonged surgery time, prolonged ventilation and critical preoperative state, followed by congestive heart failure, atrial fibrillation, renal insufficiency, stroke, peripheral vascular disease and use of an intra‐aortic balloon pump. Relatively low‐risk factors were emergent/urgent surgery, smoking, myocardial infarction, combined surgery and coronary artery bypass grafting. Sternal wound infection after open‐heart surgery is a multifactorial disease. The detected risk factors significantly affected the wound healing process, but some were different in strength. Anything that affects wound healing and antibacterial ability, such as lack of oxygen, local haemodynamic disorders, malnutrition condition and compromised immune system will increase the risk, and this reminds us of comprehensive treatment during the perioperative period.
Experimental and thermodynamic modeling study of phase equilibria in the PbO–NiO–SiO2 system
Authors: Abdeyazdan Hamed , Shevchenko Maksym , Jak Evgueni
Published: November 2023

An integrated experimental and thermodynamic modeling investigation of the phase equilibria in the PbO–NiO–SiO2 system in air and also in equilibrium with liquid metal has been undertaken to better characterize the chemical reactions taking place in the Ni‐containing Pb processing slags. New experimental phase equilibria data at 720°C–1740°C were obtained for this system using high‐temperature equilibration of synthetic mixtures with predetermined compositions in sealed silica ampoules or in Au/Pt–Ir foils, a rapid quenching technique, and electron probe x‐ray microanalysis of the equilibrated phase compositions. Phase equilibria and liquidus isotherms in the quartz/tridymite/cristobalite (SiO2), olivine (Ni2SiO4), monoxide (NiO), Ni‐barysilite (Pb8NiSi6O21), massicot (PbO), and di‐lead silicate (Pb2SiO4) primary phase fields were revealed and the extent of the high‐SiO2 two‐liquid immiscibility gap in equilibrium with cristobalite was determined. New experimental data were used in the development of a thermodynamic database describing this ternary system. Also, modeling revision of the NiO–SiO2 binary system was conducted, resulting in a smaller miscibility gap in ternary systems that was closer to the experimental results.
The origin of calcite in calc‐silicate rocks from the Kokchetav ultrahigh‐pressure metamorphic complex
Authors: Mikhno Anastasia O. , Shatskiy Anton F. , Korsakov Andrey V. , Vinogradova Yulia G. , Berndt Jasper , Klemme Stephan , Rashchenko Sergey V.
Published: November 2023

Understanding calcite genesis in ultrahigh‐pressure crustal rocks is a key to the reconstruction of the evolution of ultrahigh‐pressure metacarbonate rocks. Here, we present new data and a new model on the genesis and the P–T conditions of the formation of calcite found in the ultrahigh‐pressure calc‐silicate rocks from the Kokchetav massif. In the studied sample aragonite inclusions coexist with Type A calcite inclusions (previously interpreted as mineral inclusions) and the inclusions of Type B calcite (previously interpreted as derived from the crystallization of carbonatitic melt) in cores of garnet porphyroblasts. The most Mg‐rich calcite from Type A inclusions coexisting with aragonite inclusions in one garnet growth zone shows XCa = 0.935 implying their crystallization during a retrograde metamorphic stage at P ~ 2.3 GPa and T ~ 870°C along the P–T path. Type A calcite and aragonite inclusions were also found coexisting in one growth zone with K‐bearing clinopyroxene inclusion (ω[K2O] = 0.5 wt.%). Such a high K2O‐content in clinopyroxene testify that the pressure of inclusion capture exceeded 3.5 GPa, which contradicts the P–T conditions estimated by XCa in magnesian calcite. Thus, Type A calcite inclusions were initially captured as an aggregate of aragonite+ magnesian calcite at ultrahigh pressure metamorphic stage (P ≥ 3.5 GPa, T = 900–1,000°C) and then re‐equilibrated at lower conditions (P ≤ 2.3 GPa and T ≤ 870°C). The trace element composition of aragonite and Type A and Type B calcite from inclusions was also studied to clarify calcite genesis in these inclusions. Aragonite shows high LREE (5–57 ppm) and Sr‐content (600–800 ppm). Calcite from Type A inclusions shows low LREE (2.9–19.8 ppm) and Sr‐content (490–670 ppm). Calcite from Type B inclusions forms two groups according to the LREE and Sr content distribution (Type B1 and Type B2). Trace element distribution in Type B1 calcite is identical to that of Type A calcite, while Type B2 calcite shows high LREE (6.8–64.9 ppm) concentrations along with low Sr‐content (180–340 ppm). Type A and Type B1 calcite is interpreted to have been re‐equilibrated. Type B2 calcite inclusions crystallized from the hydrous carbonatitic melt.
Molecular evidence to support the transfer of Enteromorpha ovata to genus Ulva and evaluate its divergence using multi‐locus time‐calibrated phylogeny
Authors: Rathod Sachin G. , Anisoddin Kazi Mudassar , Mantri Vaibhav A.
Published: November 2023

Ulva has received considerable attention since its merger with tubular Enteromorpha (Linnaeus) Nees based on molecular evidence. Nevertheless, several nomenclatural and taxonomic proposals concerning tropical and subtropical species are still pending in want of investigations based on the altered circumscription and criteria of genetic diversity. Enteromorpha ovata Thivy et Visalakshmi ex H. Joshi et V. Krishnamurthy has a restricted geographical distribution only at Gopnath, India. In the present study, we for the first time provide a polyphasic approach to ascertain its taxonomic position, using morpho‐anatomy, ecology and molecular taxonomy with multigene markers (rbcL, tufA and ITS rDNA). Phylogenetic analysis based on rbcL, tufA and ITS rDNA gene sequences supported the recognition of this species within the genus Ulva. The recent revision by Kumar and Palanisamy proposed the new nomenclatural combinaton Ulva ovata (Thivy et Visalakshmi ex Joshi et Krishnamurthy) Aron Santhosh Kumar and Palanisamy, but they did not give molecular evidence while doing so, which we accomplished. Our time‐calibrated phylogeny suggested that U. ovata diverged from its respective sister lineages ~ 4.46 Mya in the Neogene period of the Cenozoic Era.
Sonography of the pituitary gland in pet rats
Authors: Pelligra Tina , Petrini Daniele , Puccinelli Caterina , Unti Serena , Citi Simonetta
Published: November 2023

Pituitary gland (PG) tumors are common in rats over the age of 2. CT and MRI can be difficult to apply in this species, whereas ultrasound is more feasible and useful. To our knowledge, there are no studies on PG ultrasound in rats. The aim of this prospective, analytical study was to evaluate the reliability of ultrasound in identifying PG, to define the ultrasound dimension of the gland in a group of rats with no evidence of pituitary diseases, and to examine its correlations with age, sex, and weight. After localizing the PG with an MRI study on one rat, the gland was identified in 21 rats by ultrasound by two sonographers using a ventral neck approach and a transversal scan with a linear probe. The gland appears as a hypoechoic oval structure with a thin hyperechoic margin. The rats (15 male and 6 female) ranged from 4 to 18 months in age (median 6 months) and from 270 to 640 g in weight (median 370 g). The median pituitary width was 3.96 mm (interquartile range 25–75%: 6–4.5 mm), and the median height was 1.48 mm (interquartile range 25–75%: 1.3–1.67 mm). There was no statistically significant correlation between PG size and rat weight, gender, or age. We believe that these ultrasound measurements could be useful for the diagnosis of pituitary disease, irrespective of whether neurological symptoms are present. We report a clinical case of a rat with a pituitary mass detected by ultrasound and CT.
Multi-Modal Machine Learning in Engineering Design: A Review and Future Directions
Authors: Song Binyang , Zhou Rui , Ahmed Faez
Published: November 2023

In the rapidly advancing field of multi-modal machine learning (MMML), the convergence of multiple data modalities has the potential to reshape various applications. This paper presents a comprehensive overview of the current state, advancements, and challenges of MMML within the sphere of engineering design. The review begins with a deep dive into five fundamental concepts of MMML: multi-modal information representation, fusion, alignment, translation, and co-learning. Following this, we explore the cutting-edge applications of MMML, placing a particular emphasis on tasks pertinent to engineering design, such as cross-modal synthesis, multi-modal prediction, and cross-modal information retrieval. Through this comprehensive overview, we highlight the inherent challenges in adopting MMML in engineering design, and proffer potential directions for future research. To spur on the continued evolution of MMML in engineering design, we advocate for concentrated efforts to construct extensive multi-modal design datasets, develop effective data-driven MMML techniques tailored to design applications, and enhance the scalability and interpretability of MMML models. MMML models, as the next generation of intelligent design tools, hold a promising future to impact how products are designed.
Atomistic mechanisms of water vapor–induced surface passivation
Authors: Chen Xiaobo , Shan Weitao , Wu Dongxiang , Patel Shyam Bharatkumar , Cai Na , Li Chaoran , Ye Shuonan , Liu Zhao , Hwang Sooyeon , Zakharov Dmitri N. , Boscoboinik Jorge Anibal , Wang Guofeng , Zhou Guangwen
Published: November 2023

The microscopic mechanisms underpinning the spontaneous surface passivation of metals from ubiquitous water have remained largely elusive. Here, using in situ environmental electron microscopy to atomically monitor the reaction dynamics between aluminum surfaces and water vapor, we provide direct experimental evidence that the surface passivation results in a bilayer oxide film consisting of a crystalline-like Al(OH)
3
top layer and an inner layer of amorphous Al
2
O
3
. The Al(OH)
3
layer maintains a constant thickness of ~5.0 Å, while the inner Al
2
O
3
layer grows at the Al
2
O
3
/Al interface to a limiting thickness. On the basis of experimental data and atomistic modeling, we show the tunability of the dissociation pathways of H
2
O molecules with the Al, Al
2
O
3
, and Al(OH)
3
surface terminations. The fundamental insights may have practical significance for the design of materials and reactions for two seemingly disparate but fundamentally related disciplines of surface passivation and catalytic H
2
production from water.
Mitochondria-targeting Cu
3
VS
4
nanostructure with high copper ionic mobility for photothermoelectric therapy
Authors: Dong Yushan , Dong Shuming , Yu Chenghao , Liu Jing , Gai Shili , Xie Ying , Zhao Zhiyu , Qin Xiran , Feng Lili , Yang Piaoping , Zhao Yanli
Published: November 2023

Thermoelectric therapy has emerged as a promising treatment strategy for oncology, but it is still limited by the low thermoelectric catalytic efficiency at human body temperature and the inevitable tumor thermotolerance. We present a photothermoelectric therapy (PTET) strategy based on triphenylphosphine-functionalized Cu
3
VS
4
nanoparticles (CVS NPs) with high copper ionic mobility at room temperature. Under near-infrared laser irradiation, CVS NPs not only generate hyperthermia to ablate tumor cells but also catalytically yield superoxide radicals and induce endogenous NADH oxidation through the Seebeck effect. Notably, CVS NPs can accumulate inside mitochondria and deplete NADH, reducing ATP synthesis by competitively inhibiting the function of complex I, thereby down-regulating the expression of heat shock proteins to relieve tumor thermotolerance. Both in vitro and in vivo results show notable tumor suppression efficacy, indicating that the concept of integrating PTET and mitochondrial metabolism modulation is highly feasible and offers a translational promise for realizing precise and efficient cancer treatment.
The yeast prion protein Sup35 initiates α-synuclein pathology in mouse models of Parkinson’s disease
Authors: Meng Lanxia , Liu Congcong , Li Yiming , Chen Guiqin , Xiong Min , Yu Ting , Pan Lina , Zhang Xingyu , Zhou Lingyan , Guo Tao , Yuan Xin , Liu Chaoyang , Zhang Zhaohui , Zhang Zhentao
Published: November 2023

Parkinson’s disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with
Saccharomyces cerevisiae
(
S. cerevisiae
) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from
S. cerevisiae
, is the key factor initiating α-syn pathology induced by
S. cerevisiae
. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.
Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma
Authors: Khang Minsoo , Lee Ju Hyun , Lee Teresa , Suh Hee-Won , Lee Supum , Cavaliere Alessandra , Rushing Amy , Geraldo Luiz H. , Belitzky Erika , Rossano Samantha , de Feyter Henk M. , Shin Kwangsoo , Huttner Anita , Roussel Martine F. , Thomas Jean-Leon , Carson Richard E. , Marquez-Nostra Bernadette , Bindra Ranjit S. , Saltzman W. Mark
Published: November 2023

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.
Retroviral hijacking of host transport pathways for genome nuclear export
Authors: Behrens Ryan T. , Sherer Nathan M.
Published: November 2023

Recent advances in the study of virus-cell interactions have improved our understanding of how viruses that replicate their genomes in the nucleus (e.g., retroviruses, hepadnaviruses, herpesviruses, and a subset of RNA viruses) hijack cellular pathways to export these genomes to the cytoplasm where they access virion egress pathways. These findings shed light on novel aspects of viral life cycles relevant to the development of new antiviral strategies and can yield new tractable, virus-based tools for exposing additional secrets of the cell. The goal of this review is to summarize defined and emerging modes of virus-host interactions that drive the transit of viral genomes out of the nucleus across the nuclear envelope barrier, with an emphasis on retroviruses that are most extensively studied. In this context, we prioritize discussion of recent progress in understanding the trafficking and function of the human immunodeficiency virus type 1 Rev protein, exemplifying a relatively refined example of stepwise, cooperativity-driven viral subversion of multi-subunit host transport receptor complexes.
The nonstructural protein 1 of respiratory syncytial virus hijacks host mitophagy as a novel mitophagy receptor to evade the type I IFN response in HEp-2 cells
Authors: Cheng Jing , Wang Yutong , Yin Lizheng , Liang Wenzhang , Zhang Jing , Ma Cuiqing , Zhang Yu , Liu Bo , Wang Jiachao , Zhao Weiting , Li Miao , Wei Lin
Published: November 2023

Mitochondria are good targets for viruses to manipulate their hosts. However, it remains obscure whether respiratory syncytial virus (RSV) target mitochondria to suppress the type I interferon (IFN) responses. Here, we show that nonstructural protein 1 (NS1) protein of RSV interacts with Tu translation elongation factor mitochondrial (TUFM), which can lead to its localization in mitochondria and finally induce TUFM-dependent mitophagy and inhibition of IFNβ. Mechanically, NS1-mediated TUFM-dependent mitophagy does not depend on the PINK1-PARKIN pathway and classic mitophagy receptors. Importantly, NS1 may act as a new receptor protein to bridge mitochondria and autophagosomes by interacting with TUFM and LC3B. The LIR motif of NS1 protein is essential for its interaction with LC3B and is of great importance for its mitophagy induction and IFNβ suppression. Finally, NS1-induced TUFM-dependent mitophagy was essential for its attenuated IFNβ response using autophagy-deficient cells and mice. Our study provides a novel mitophagy receptor molecular and a new antiviral option by suppressing antiviral innate immune via targeting TUFM-dependent mitophagy.

IMPORTANCE

It is a worthy concern for us to understand virus-host interactions which affect progression and prognosis of disease. We demonstrated that the non-structural protein 1 of respiratory syncytial virus (RSV NS1) may act as a novel mitophagy receptor to induce mitophagy by binding LC3B and mitochondrial protein TUFM, and finally dampen interferon (IFN) responses induced by RIG1 and RSV infection. TUFM is beneficial for RSV replication
in vivo
and
vitro
. It is new and interesting that RSV NS1 may function as a mitophagy receptor to interact with LC3B. The LIR motif of NS1 protein is essential for its interaction with LC3B. We further confirm that RSV NS1 inhibited IFNβ response and promoted RSV replication in autophagy-dependent mechanisms
in vivo
and
vitro
. Our study contributes to understanding virus-host interaction, enriching our insights into RSV pathogenic mechanism and exploiting new antiviral treatments targeting TUFM.
Aedes aegypti
D7 long salivary proteins modulate blood feeding and parasite infection
Authors: Martin-Martin Ines , Kojin Bianca Burini , Aryan Azadeh , Williams Adeline E. , Molina-Cruz Alvaro , Valenzuela-Leon Paola Carolina , Shrivastava Gaurav , Botello Karina , Minai Mahnaz , Adelman Zach N. , Calvo Eric
Published: November 2023

Mosquito saliva facilitates blood meal acquisition through pharmacologically active compounds that prevent host hemostasis and immune responses. Here, we generated two knockout (KO) mosquito lines by CRISPR/Cas9 to functionally characterize D7L1 and D7L2, two abundantly expressed salivary proteins from the yellow fever mosquito vector
Aedes aegypti
. The D7s bind and scavenge biogenic amines and eicosanoids involved in hemostasis at the bite site. The absence of D7 proteins in the salivary glands of KO mosquitoes was confirmed by mass spectrometry, enzyme-linked immunosorbent assay, and fluorescence microscopy of the salivary glands with specific antibodies. D7-KO mosquitoes had longer probing times than parental wildtypes. The differences in probing time were abolished when mutant mice resistant to inflammatory insults were used. These results confirmed the role of D7 proteins as leukotriene scavengers
in vivo
. We also investigated the role of D7 salivary proteins in
Plasmodium gallinaceum
infection and transmission. Both KO lines had significantly fewer oocysts per midgut. We hypothesize that the absence of D7 proteins in the midgut of KO mosquitoes might be responsible for creating a harsh environment for the parasite. The information generated by this work highlights the biological functionality of salivary gene products in blood feeding and pathogen infection.

IMPORTANCE

During blood feeding, mosquitoes inject saliva into the host skin, preventing hemostasis and inflammatory responses. D7 proteins are among the most abundant components of the saliva of blood-feeding arthropods.
Aedes aegypti
, the vector of yellow fever and dengue, expresses two D7 long-form salivary proteins: D7L1 and D7L2. These proteins bind and counteract hemostatic agonists such as biogenic amines and leukotrienes. D7L1 and D7L2 knockout mosquitoes showed prolonged probing times and carried significantly less
Plasmodium gallinaceum
oocysts per midgut than wild-type mosquitoes. We hypothesize that reingested D7s play a vital role in the midgut microenvironment with important consequences for pathogen infection and transmission.
Genome-sequenced bacterial collection from sorghum epicuticular wax
Authors: Mechan-Llontop Marco E. , Mullet John , Shade Ashley
Published: November 2023

A collection of 44 isolates isolated from the epicuticular wax of stems of energy sorghum is available at the Great Lakes Bioenergy Researcher Center, Michigan State University, MI, USA. We enriched bacteria with putative plant-beneficial phenotypes and include information on their phenotypic diversity, taxonomy, and whole-genome sequences.
Single-cell quantitative bioimaging of
P. berghei
liver stage translation
Authors: McLellan James L. , Sausman William , Reers Ashley B. , Bunnik Evelien M. , Hanson Kirsten K.
Published: November 2023

Plasmodium
parasite resistance to existing antimalarial drugs poses a devastating threat to the lives of many who depend on their efficacy. New antimalarial drugs and novel drug targets are in critical need, along with novel assays to accelerate their identification. Given the essentiality of protein synthesis throughout the complex parasite lifecycle, translation inhibitors are a promising drug class, capable of targeting the disease-causing blood stage of infection, as well as the asymptomatic liver stage, a crucial target for prophylaxis. To identify compounds capable of inhibiting liver stage parasite translation, we developed an assay to visualize and quantify translation in the
Plasmodium berghei-
HepG2 infection model. After labeling infected monolayers with o-propargyl puromycin (OPP), a functionalized analog of puromycin permitting subsequent bioorthogonal addition of a fluorophore to each OPP-terminated nascent polypeptide, we use automated confocal feedback microscopy followed by batch image segmentation and feature extraction to visualize and quantify the nascent proteome in individual
P. berghei
liver stage parasites and host cells simultaneously. After validation, we demonstrate specific, concentration-dependent liver stage translation inhibition by both parasite-selective and pan-eukaryotic active compounds and further show that acute pre-treatment and competition modes of the OPP assay can distinguish between known direct translation inhibitors and other compounds which we identify as indirect translation inhibitors. Using this framework, we identify a Malaria Box compound, MMV019266, as a direct translation inhibitor in
P. berghei
liver stages and confirm this potential mode of action in
Plasmodium falciparum
asexual blood stages.

IMPORTANCE

Plasmodium
parasites cause malaria in humans. New multistage active antimalarial drugs are needed, and a promising class of drugs targets the core cellular process of translation, which has many potential molecular targets. During the obligate liver stage,
Plasmodium
parasites grow in metabolically active hepatocytes, making it challenging to study core cellular processes common to both host cells and parasites, as the signal from the host typically overwhelms that of the parasite. Here, we present and validate a flexible assay to quantify
Plasmodium
liver stage translation using a technique to fluorescently label the newly synthesized proteins of both host and parasite followed by computational separation of their respective nascent proteomes in confocal image sets. We use the assay to determine whether a test set of known compounds are direct or indirect liver stage translation inhibitors and show that the assay can also predict the mode of action for novel antimalarial compounds.
Limitation of amino acid availability by bacterial populations during enhanced colitis in IBD mouse model
Authors: Richie Tanner G. , Heeren Leah , Kamke Abigail , Monk Kourtney , Pogranichniy Sophia , Summers Trey , Wiechman Hallie , Ran Qinghong , Sarkar Soumyadev , Plattner Brandon L. , Lee Sonny T. M.
Published: November 2023

Members of the Enterobacteriaceae and
Enterococcus
are associated with persistent gut inflammation due to rapid colonization combined with pathogenic tendencies. Here, we investigated the functions of gut microbial populations resulting in persistent gut inflammation. In this study, we utilized the IL-10 knockout mouse model and induced colitis using dextran sulfate sodium (2%) after development. Dams during gestation were provided cefoperazone to induce vertically transmitted dysbiosis in the pups that were monitored in this study. We characterized the dysbiotic gut microbial community and potential crosstalk of these microbes, and host gene expression changes to identify bacterial populations and potential functions that were involved in gut inflammation. We isolated Enterobacteriaceae populations from mice to validate the utilization of sulfur-containing amino acids. Members of Enterobacteriaceae and
Enterococcus
were highly detected in inflamed mice. Enterobacteriaceae populations containing L-cysteine dioxygenase were strongly correlated with the upregulation of host gene
CSAD
, responsible for cysteine breakdown. We observed that bacterial isolates from dysbiotic mice displayed increased growth rates when supplemented with L-cysteine, highlighting the use of sulfur metabolism. Our results show that microbial populations use alternate metabolisms and sequester host nutrients for growth, associated with inflammation in the gut.

IMPORTANCE

Inflammatory bowel disease is associated with an increase in Enterobacteriaceae and Enterococcus species; however, the specific mechanisms are unclear. Previous research has reported the associations between microbiota and inflammation, here we investigate potential pathways that specific bacteria populations use to drive gut inflammation. Richie et al. show that these bacterial populations utilize an alternate sulfur metabolism and are tolerant of host-derived immune-response products. These metabolic pathways drive host gut inflammation and fuel over colonization of these pathobionts in the dysbiotic colon. Cultured isolates from dysbiotic mice indicated faster growth supplemented with L-cysteine, showing these microbes can utilize essential host nutrients.
Ribosome profiling reveals the fine-tuned response of
Escherichia coli
to mild and severe acid stress
Authors: Schumacher Kilian , Gelhausen Rick , Kion-Crosby Willow , Barquist Lars , Backofen Rolf , Jung Kirsten
Published: November 2023

The ability to respond to acidic environments is crucial for neutralophilic bacteria.
Escherichia coli
has a well-characterized regulatory network that triggers a multitude of defense mechanisms to counteract excess protons. Nevertheless, systemic studies of the transcriptional and translational reprogramming of
E. coli
to different degrees of acid stress have not yet been performed. Here, we used ribosome profiling and RNA sequencing to compare the response of
E. coli
(pH 7.6) to sudden mild (pH 5.8) and severe near-lethal acid stress (pH 4.4) conditions that mimic passage through the gastrointestinal tract. We uncovered new differentially regulated genes and pathways, key transcriptional regulators, and 18 novel acid-induced candidate small open reading frames. By using machine learning and leveraging large compendia of publicly available
E. coli
expression data, we were able to distinguish between the response to acid stress and general stress. These results expand the acid resistance network and provide new insights into the fine-tuned response of
E. coli
to mild and severe acid stress.

IMPORTANCE

Bacteria react very differently to survive in acidic environments, such as the human gastrointestinal tract.
Escherichia coli
is one of the extremely acid-resistant bacteria and has a variety of acid-defense mechanisms. Here, we provide the first genome-wide overview of the adaptations of
E. coli
K-12 to mild and severe acid stress at both the transcriptional and translational levels. Using ribosome profiling and RNA sequencing, we uncover novel adaptations to different degrees of acidity, including previously hidden stress-induced small proteins and novel key transcription factors for acid defense, and report mRNAs with pH-dependent differential translation efficiency. In addition, we distinguish between acid-specific adaptations and general stress response mechanisms using denoising autoencoders. This workflow represents a powerful approach that takes advantage of next-generation sequencing techniques and machine learning to systematically analyze bacterial stress responses.
Cbl-b negatively regulates TLR/MyD88-mediated anti-
Toxoplasma gondii
immunity
Authors: Wei Haixia , Wu Shuizhen , Mai Liying , Yang Lili , Zou Weihao , Peng Hongjuan
Published: November 2023

Toxoplasma gondii
is an important intracellular protozoan, which needs to exploit host nutrition for successful parasitism. We previously reported that Casitas B-lineage lymphoma-b (Cbl-b) was screened as a host dependency factor of
T. gondii
by using lentiviral CRISPR-Cas9-single guide RNA (sgRNA) libraries. Furthermore, the detailed mechanism of Cbl-b being required by
T. gondii
infection was explored in this study. The proliferation of
T. gondii
was found to be significantly inhibited in Cbl-b knockdown cell lines, and the Cbl-b expression level increased with prolonged
T. gondii
infection, while the MyD88 level was significantly decreased in the
T. gondii
infection group. Toll-like receptor (TLR)/MyD88 is a conserved innate cellular immune signaling pathway against pathogens infection. Cbl-b was found to interact with MyD88 and mediate MyD88 ubiquitination in the fluorescence resonance energy transfer and co-immunoprecipitation experiments. A Cbl-b knockout (KO) C57BL/6J lineage was then constructed and, together with the wild-type (WT) mice, was infected with the same amount of
T. gondii
tachyzoites of ME49 strain. At 13 days post infection, all the mice in the WT group died, while 80% of the mice in the Cbl-b KO group still survived, even to the end of the experiment. The parasitic burden in the liver, lung, and brain of the Cbl-b KO mice was significantly lower than that of the WT mice (
P
< 0.05). In Cbl-b KO infected mice, the percentage of B cells was higher, whereas that of macrophages was lower, and the interferon-γ and interleukin-6 levels in the serum were higher than that in the WT infected mice; the difference was significant (
P
< 0.05). Furthermore, when host cells were infected by
T. gondii
, host’s Cbl-b was found to interact with MyD88 to ubiquitinate MyD88 for ribosome-dependent degradation. Therefore, the host’s innate immunity against
T. gondii
through the TLR/MyD88 pathway was negatively regulated by Cbl-b.

IMPORTANCE

This is the first report that a human E3 ubiquitin ligase, Casitas B-lineage lymphoma proto-oncogene B (Cbl-b), functions as a host dependency factor for the intracellular protozoan
Toxoplasma gondii
and the mechanism for how
T. gondii
infection inhibits the TLR/MyD88 innate immunity pathway through MyD88 degradation mediated by Cbl-b. This finding is an impactful contribution for understanding the host cell immunity against
T. gondii
infection.