bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of tyrosine kinase inhibitors for advanced metastatic thyroid cancer: A systematic review and network meta-analysis of randomized controlled trials
Authors: Zhao Mingjian , Li Ruowen , Song Zhimin , Miao Chengxu , Lu Jinghui
Published: April 2024

Background:

Tyrosine kinase inhibitors (TKIs) have been approved for treating patients with clinically advanced metastatic thyroid cancer. However among the many TKIs, it remains unknown which regimen is the best choice for these patients.

Methods:

We conducted a systematic review and network meta-analysis to compare the survival benefits and efficacy of the available first-line regimens. We conducted an active search for phase II, III, or IV randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to compare the effects of at least 2 drugs in the systemic treatment of advanced or metastatic thyroid cancer up to May 2023. The network meta-analysis model was adjusted using Bayesian Network model. Twelve trials with 2535 patients were included in our meta-analysis. The overall survival (OS), progression-free survival (PFS), and serious adverse events (SAEs) were taken as reference indicators. We also performed subgroup analyses of OS and PFS in medullary thyroid cancer (MTC) and radioiodine-refractory differentiated thyroid cancer (RR-DTC) to explore the variations of TKIs in different groups.

Results:

As a result, apatinib had the best effect on overall survival (OS) (hazards ratio [HR] = 0.42, 95% confidence interval [CI] = 0.18–0.98), lenvatinib 18 mg/d has the best effect on progression-free survival (PFS) (HR = 0.13, 95% CI = 0.064–0.27), and cabozantinib 60 mg/d has the best safety profile.

Conclusions:

Our network meta-analysis showed that we believe that cabozantinib has the potential to become a widely used drug in clinical practice.
Exploring the profound link: Breastfeeding’s impact on alleviating the burden of breast cancer – A review
Authors: Obeagu Emmanuel Ifeanyi , Obeagu Getrude Uzoma
Published: April 2024

Breastfeeding has emerged as a critical factor in understanding and potentially mitigating the risk of breast cancer among women. This review delves into the intricate relationship between breastfeeding and breast cancer, elucidating the biological mechanisms, protective effects, and broader implications for public health. Epidemiological evidence consistently demonstrates a correlation between breastfeeding and a reduced risk of breast cancer, with longer durations of lactation showing a dose-dependent decrease in risk. The biological nexus between breastfeeding and breast cancer involves hormonal changes and the elimination of potentially damaged cells, influencing breast tissue and potentially mitigating carcinogenesis. Moreover, breastfeeding appears to impact tumor subtypes and aggressiveness, particularly demonstrating associations with lower risks of hormone receptor-negative and certain aggressive breast cancer subtypes. Recognizing the significance of breastfeeding in reducing breast cancer risk has profound public health implications, necessitating comprehensive support, education, and policies to encourage and facilitate breastfeeding.
Bilateral sinonasal inverted papillomas originating from both sides of the frontal sinus and the left lamina papyracea: A case report
Authors: Li Yang , Ma Dengdian
Published: April 2024

Rationale:

The present investigation documented a case of bilateral sinonasal inverted papilloma (SNIP) that arose from both sides of the frontal sinus and ethmoid sinus. The occurrence of bilateral involvement of the nasal cavities and frontal sinus is rather infrequent.

Patient concerns:

Informed consent was obtained from the patient.

Diagnosis:

Bilateral SNIP.

Interventions:

The tumor was completely removed by Draf III endoscopic resection complemented by an external eyebrow arch approach, and the postoperative recovery was uneventful.

Outcomes:

The purpose of this paper is to present a comprehensive reference for the management of bilateral SNIP that affects the frontal sinuses.

Lessons:

This study addresses the staging and surgical management of bilateral SNIP, along with a review of the factors contributing to its recurrence. The recommended treatment method involves applying the Draf III technique combined with an external nasal approach.
Effects of low fat diet on inflammatory parameters in individuals with obesity/overweight and non-alcoholic fatty liver disease: A cross-sectional study
Authors: Erdem Nur Bengü , Kahramanoğlu Aksoy Evrim , Dikmen Derya , Uçar Baş Kübra , Ağaçdiken Aslihan , İlhan Esgin Merve , Göktaş Zeynep
Published: April 2024

Nonalcoholic fatty liver disease (NAFLD) is considered one of the most important causes of chronic liver disorders in the world. Dietary pattern is a modifiable risk factor that represents the main target for the prevention and treatment of NAFLD. The aim of this cross-sectional study was to assess the impact of low-fat diet on anthropometric measurements, biochemical, and inflammatory parameters in individuals with obesity/overweight and NAFLD. A total of 108 individuals (n = 59 males and n = 49 females) aged between 19 and 65 years participated in the 12-week weight loss program. Dietary treatment plans including low-fat diets were randomly prescribed for each individual. Anthropometric measurements were collected by a trained dietitian at baseline and 12-week follow-up. Blood samples were collected for each individual at baseline and 3rd month for biochemical measurements and enzyme-linked immunosorbent assay analysis for tumor necrosis factor-α (TNF-α), interleukin (IL)-6, fibroblast growth factor-21 (FGF-21), chemerin, and irisin levels in plasma. At the end of the study, body weight, body mass index, body fat % body fat mass (kg) reduced significantly in females and males (P < .05). Moreover, reductions in waist, hip, and neck circumferences were significant in both groups. Changes in alanine aminotransferase and aspartate aminotransferase levels were significant in 3rd month. After 3 months, reductions in TNF-α, IL-6, and FGF-21 levels were significant in individuals with obesity/overweight and NAFLD. While no significant change in chemerin and irisin levels was found. These results show that low-fat diet over a 12-week period led to improvements in both anthropometric measurements and biochemical parameters in individuals with obesity/overweight and NAFLD.
A relatively rare traditional Chinese medicine pattern of primary Sjögren syndrome: A case report
Authors: Chen Qiang , Chen Xinru , Zhu Yuqing , Yu Xiali
Published: April 2024

Rationale:

This report presents a unique case of a patient diagnosed with Primary Sjögren’s syndrome and a relatively rare traditional Chinese medicine pattern, known as the combined cold and heat pattern and cold-dampness syndrome. The patient’s condition was successfully managed using Chinese herbal medicine, specifically the modified Da-Chai-Hu decoction and Linggui Zhugan decoction.

Patient concerns:

A 56-year-old woman had chronic dry eye and mouth for over 10 years. She was initially managed with traditional Chinese herbal medicine (TCHM) prescriptions, including the Zengye decoction, but the therapeutic effects were unsatisfactory. As the disease progressed, she was diagnosed with an anxiety disorder due to symptoms of vexation and insomnia. Treatment with alprazolam and venlafaxine failed to alleviate these symptoms. Recently, her general condition gradually worsened, with symptoms including a bitter taste in her mouth, dizziness, hot flashes, chills, poor appetite, chest discomfort, and constipation.

Diagnoses:

After a series of examinations, including a Schirmer test and labial gland biopsy, she was diagnosed with Sjögren’s syndrome.

Interventions:

Despite regular treatment with pilocarpine, sodium hyaluronate eye drops, venlafaxine, and alprazolam, the dry mouth symptoms intensified. Consequently, she sought further intervention through the TCHM.

Outcomes:

After 8 weeks of treatment with the modified Da-Chai-Hu decoction and Linggui Zhugan decoction, she reported a significant improvement in her dryness-related symptoms and sleep quality.

Lessons:

This case report demonstrates that TCHM can effectively treat Primary Sjögren’s syndrome, and should be considered for broader applications. Furthermore, this underscores the importance of tailoring treatment formulas to patients by identifying their specific syndrome differentiation in a clinical setting.
Prevalence and correlates of medical student mistreatment in Nigeria: A narrative review
Authors: Essien Emmanuel Aniekan , Ukoaka Bonaventure Michael , Daniel Faithful Miebaka , Okobru Gideon , Adam Tajuddeen Wali
Published: April 2024

Mistreatment in medical education encompasses various forms of abusive behavior, often indicating a disregard for students’ dignity and interfering with the learning process. This review paper aims to investigate the prevalence, patterns, and correlates of medical student mistreatment in Nigerian medical education and shed light on its impact on students’ well-being. A literature search was conducted in August 2023 using Medline, Google Scholar, and Web of Science databases to identify relevant studies on the mistreatment of Nigerian medical students. Inclusion criteria encompassed all studies written in English, regardless of study design, while editorials, reviews, and opinion articles were excluded. Six studies with a total sample size of 1432 were included in the review. The review revealed high mistreatment rates, ranging from 46% to 91%, with verbal abuse being the most common form. Male students were more likely to experience mistreatment, while females had higher rates of sexual abuse. Perpetrators included male and female healthcare professionals, with consultants and resident doctors as common perpetrators. Age and study level were associated with mistreatment experiences. Consequences of mistreatment included emotional distress, depression, loss of self-confidence, academic disillusionment, substance abuse, and suicidal thoughts. Reporting rates were low due to a lack of awareness, fear of reprisal, and perceived futility. The findings underscore the need for institutions to create a supportive environment, raise awareness of available support systems, and implement policies to prevent mistreatment. Future research should focus on larger-scale studies with diverse samples and longitudinal designs to address limitations in the current literature.
Risk factors for postoperative bleeding following endoscopic submucosal dissection in early gastric cancer: A systematic review and meta-analysis
Authors: Gu Yuanbo , Zhao Shuchang
Published: April 2024

Background:

Early gastric cancer (EGC) presents a significant challenge in surgical management, particularly concerning postoperative bleeding following endoscopic submucosal dissection. Understanding the risk factors associated with postoperative bleeding is crucial for improving patient outcomes.

Methods:

Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review and meta-analysis were conducted across PubMed, Embase, Web of Science, and the Cochrane Library without publication date restrictions. The inclusion criteria encompassed observational studies and randomized controlled trials focusing on EGC patients undergoing endoscopic submucosal dissection and their risk factors for postoperative bleeding. The Newcastle-Ottawa Scale was utilized for quality assessment. The effect size was calculated using random or fixed-effects models based on the observed heterogeneity. We assessed the heterogeneity between studies and conducted a sensitivity analysis.

Results:

In our meta-analysis, 6 studies involving 4868 EGC cases were analyzed. The risk of postoperative bleeding was notably increased with intraoperative ulcer detection (odds ratio: 1.97, 95% confidence interval [CI]: 1.03–3.76, I
2 = 61.0%, P = .025) and antithrombotic medication use (odds ratio: 2.02, 95% CI: 1.16–3.51, I
2 = 57.2%, P = .039). Lesion resection size showed a significant mean difference (5.16, 95% CI: 2.97–7.98, P < .01), and longer intraoperative procedure time was associated with increased bleeding risk (mean difference: 11.69 minutes, 95% CI: 1.82–26.20, P < .05). Sensitivity analysis affirmed the robustness of these findings, and publication bias assessment indicated no significant bias.

Conclusions:

In EGC treatment, the risk of post-endoscopic submucosal dissection bleeding is intricately linked to factors like intraoperative ulcer detection, antithrombotic medication use, the extent of lesion resection, and the length of the surgical procedure. These interwoven risk factors necessitate careful consideration and integrated management strategies to enhance patient outcomes and safety in EGC surgeries.
Predictors of health workers’ knowledge of maternal and perinatal deaths surveillance and response system in Morogoro region, Tanzania: An analytical cross-sectional study
Authors: Kashililika Christina , Millanzi Walter C. , Moshi Fabiola Vincent
Published: April 2024

This study aimed at assessing the predictors of knowledge about the Maternal and Perinatal Deaths Surveillance and Response (MPDSR) system among health workers in the Morogoro region. It was an analytical cross-sectional study, conducted from April 27 to May 29, 2020. A multistage sampling technique was used to recruit 360 health workers. A semi-structured questionnaire was used to collect the data. Statistical Package for Social Science (SPSS v.20) software was used for data entry and analysis. Bivariate and multivariate logistic regression analyses were used to assess factors associated with knowledge of MPDSR. A total of 105 (29.2%) health workers in the Morogoro region had adequate knowledge of the MPDSR system. After controlling for confounders, predictors of knowledge on the MPDSR system were the level of health facility a health worker was working (n [hospital [adjusted odds ratio [AOR] = 2.668 at 95% confidence intervals [CI] = 1.497–4.753, P = .001]), level of education of a health worker (diploma [AOR = 0.146 at 95% CI = 0.038–0.561, P = .005]), and status of training on MPDSR (trained [AOR = 7.253 at 95% CI = 3.862–13.621, P ≤ .001]). The proportion of health workers with adequate knowledge about the MPDSR system in the Morogoro region is unacceptably low. Factors associated with adequate knowledge were those working in hospitals with higher levels of professional training and those who had ever had training in MPDSR. A cost-effective strategy to improve the level of knowledge regarding MPDSR in this region is highly recommended.
Diagnostic value of contrast-enhanced ultrasound in the diagnosis of papillary thyroid microcarcinoma: A systematic review and meta-analysis
Authors: Ding Yan , Peng Yulan , Zhang Jing , Pan Xueqin , Huang Xu , Zhang Chun-Quan
Published: April 2024

Background:

Using meta-analysis to evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in the diagnosis of papillary thyroid microcarcinoma (PTMC).

Methods:

For this systematic review and meta-analysis, we searched PubMed, Cochrane Library, Web of Science, WanFang Data, VPCS Data, and China National Knowledge Infrastructure electronic databases for diagnostic studies on PTMC by CEUS from January 2013 to November 2022. Data were not available or incomplete such as case reports, nonhuman studies, etc, were excluded. Random-effects meta-analyses were used to evaluate the diagnostic accuracy of CEUS in diagnosing PTMC. The quality of the evidence was assessed with the QUADAS-2 scale. This study is registered on PROSPERO, number CRD42023409417.

Results:

Of 1064 records identified, 33 were eligible. The results showed that the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of CEUS in diagnosing PTMC were 0.84 (95% confidence interval [CI] = 0.83–0.86), 0.82 (95% CI = 0.80–0.83), 3.90 (95% CI = 3.23–4.72), 0.21 (95% CI = 0.18–0.25), and 20.01 (95% CI = 14.97–26.74), respectively, and the area under the summary receiver operating characteristic curve was 0.8930 (the Q index was 0.8239). The Deek funnel plot indicated publication bias (P ˂.01).

Conclusion:

This meta-analysis provides an overview of diagnostic accuracy of CEUS in diagnosing PTMC which indicates CEUS has a good diagnostic value for PTMC. The limitations of this study are publication bias and strong geographical bias.
Impact of pulmonary rehabilitation on patients with different chronic respiratory diseases during hospitalization
Authors: Shi Xin-Yu , Ren Yi , Gu Xiao-Meng , Jia Yan-Rui , Wang Xue
Published: April 2024

The impact of pulmonary rehabilitation (PR) on patients with different chronic respiratory diseases (CRDs) during hospitalization has not been thoroughly evaluated before. The objectives of the current research were to assess the effect of comprehensive PR management on inpatients’ self-management skills, exercise capacity, nutrition assessment and mental health issues and explore whether impacts of PR vary in different CRDs. This retrospective study analyzed the clinical data from 272 inpatients with CRDs receiving PR management during hospitalization between October 2020 and March 2022 in Beijing Chao-Yang Hospital. Significant improvements were found in the patients’ ability of daily living (ADL), dyspnea (assessed by modified medical research council dyspnea scale (MMRC)), handgrip strength, maximal inspiratory and expiratory pressure, anxiety (using the 7-item generalized anxiety disorder scale (GAD-7)) and depression (the 9-item patient health questionnaire score (PHQ-9)). There was no significant change in nutrition assessment pre-post PR management during hospitalization. The subgroup analyses were conducted on hospitalized patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, asthma, interstitial lung diseases (ILDs) and other CRDs (e.g., lung cancer, diaphragm hemiparesis, obesity, etc.). The results showed that ADL, MMRC score, MIP, MEP, PHQ-9 score improved in all subgroups with CRDs. Handgrip strength of left hand was increased in COPD inpatients and anxiety was improved in all subgroups except for ILDs. Comprehensive PR management was necessary and beneficial for patients with different CRDs during hospitalization.
Mandible elemental composition and mechanical properties from distinct castes of the leafcutter ant
Atta laevigata
(Attini; Formicidae)
Authors: Birkenfeld Valentin , Gorb Stanislav N. , Krings Wencke
Published: April 2024

Leafcutter ant colonies are divided into castes with the individuals performing different tasks, based mostly on size. With the mandibles, the small minims care for the brood or the fungus, whereas the larger minors and mediae cut and transport plant material, with the ant size positively related to the material size. The mechanical properties and composition of the mandible cuticle have been previously tested in the soldiers as the largest caste, revealing that the cutting edges contained high contents of the cross-linking transition metal zinc (Zn). With regard to the smaller castes, no data are present. To study how the mandible size and function relates to its mechanical properties, we here tested the mandibles of minims, minors and mediae by nanoindentation. We found that the hardness (H) and Young's modulus (E) values increased with increasing ant size and that the mandible cutting edges in each caste have the highest H- and E-values. To gain insight into the origins of these properties, we characterized the elemental composition by energy-dispersive X-ray analysis, revealing that minors and mediae possessed higher content of Zn in the cutting edges in contrast to the minims containing significantly less Zn. This shows, that Zn content relates to higher mechanical property values. Additionally, it shows that all of these parameters can differ within a single species.
Wear patterns of radular teeth in
Loligo vulgaris
(Cephalopoda; Mollusca) are related to their structure and mechanical properties
Authors: Hackethal Svenja , Schulz-Kornas Ellen , Gorb Stanislav N. , Krings Wencke
Published: April 2024

Radular teeth have to cope with wear, when interacting with ingesta. In some molluscan taxa, wear-coping mechanisms, related to the incorporation of high contents of iron or silica, have been previously determined. For most species, particularly for those which possess radulae without such incorporations, wear-coping mechanisms are understudied. In the present study, we documented and characterized the wear on radular teeth in the model species
Loligo vulgaris
(Cephalopoda). By applying a range of methods, the elementary composition and mechanical properties of the teeth were described, to gain insight into mechanisms for coping with abrasion. It was found that the tooth regions that are prone to wear are harder and stiffer. Additionally, the surfaces interacting with the ingesta possessed a thin coating with high contents of silicon, probably reducing abrasion. The here presented data may serve as an example of systematic study of radular wear, in order to understand the relationship between the structure of radular teeth and their properties.
Reduced selection during sweeps lead to adaptive momentum on rugged landscapes
Authors: Bohm Clifford , Ragusa Vincent R. , Ofria Charles , Lenski Richard E. , Adami Christoph
Published: April 2024

Abstract

Evolutionary theory seeks to explain the remarkable diversity and adaptability of life on Earth. Current theory offers substantial explanatory power, but it overlooks important transient dynamics that are prominent only when populations are outside equilibrium, such as during selective sweeps. We identify a dynamic that we call “adaptive momentum” whereby lineages with a selective advantage can temporarily sustain more deleterious mutations. This reduction in the strength of purifying selection allows populations to explore fitness valleys that are usually too costly to enter, potentially leading to the discovery of otherwise inaccessible fitness peaks. Using mathematical and agent-based simulations, we demonstrate adaptive momentum and show how periods of disequilibrium become windows of enhanced adaptation. Genetic exploration can occur during these windows without requiring mechanisms such as changing environments or complex landscapes. Adaptive momentum provides a simple potential explanation for bursts of rapid evolution observed in nature, including in pathogens such as SARS-CoV-2 and cancers. (152 words)
Defective Homologous Recombination and Genomic Instability Predict Increased Responsiveness to Carbon Ion Radiotherapy in Pancreatic Cancer
Authors: Sishc Brock J. , Saha Janapriya , Polsdofer Elizabeth , Ding Lianghao , Lu Huiming , Wang Shih-Ya , Swancutt Katy L. , Nicholson James H. , Facoetti Angelica , Pompos Arnold , Ciocca Mario , Aguilera Todd A. , Story Michael D. , Davis Anthony J.
Published: April 2024

Pancreatic ductal adenocarcinoma (PDAC) is inherently resistant to conventional chemo-and radiation-therapy. However, clinical trials showed that carbon ion radiotherapy (CIRT) with concurrent gemcitabine can be effective for treating unresectable locally advanced PDAC. In this study, we aimed to determine features that could identify patients who would benefit most from CIRT. A panel of human PDAC cell lines with various genetic backgrounds was leveraged to determine whether a subset could be identified that preferentially responds to CIRT. The cell lines displayed a differential response to CIRT as compared to γ-rays as measured by relative biological effectiveness (RBE) calculated at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity correlated with decreased DNA double strand break (DSB) repair as measured by γH2AX foci resolution. We determined that the cell lines most sensitive to CIRT are defective in the homologous recombination (HR) DSB repair pathway and/or have high genomic instability due to elevated replication stress. Next, this knowledge was utilized to assess whether the HR pathway could be targeted to potentiate CIRTin vitro. It was determined that pretreating a radioresistant PDAC cell line with the HR inhibitor, B02, resulted in a marked increase in sensitivity to CIRT when treated with high linear energy transfer (LET) radiation in the spread-out Bragg peak (74.1-89.3 keV/μm) but not at the entry LET (13.0-16.4 keV/μm)in vitroas opposed to that seen with a NHEJ inhibitor. These data suggest a greater therapeutic index with the combination therapy in the tumor over normal tissues based on LET distribution. These data support the notion that PDAC tumors with defects in HR and/or those with high inherent replication stress respond to CIRT without the concern for excessive normal tissue toxicity. With the advent of agents targeting HR, the difference in tumor cell response in the entry region vs within the SOBP based upon the respective LETs of those regions of the beam profile, will be superior to agents that target NHEJ.
Paradigms of convergent evolution in enzymes
Authors: Riziotis Ioannis G. , Kafas Jenny C. , Ong Gabriel , Borkakoti Neera , Ribeiro Antonio J.M. , Thornton Janet M.
Published: April 2024

There are many occurrences of enzymes catalysing the same reaction but having significantly different structures. Leveraging the comprehensive information on enzymes stored in the Mechanism and Catalytic Site Atlas (M-CSA), we present a collection of 38 cases for which there is sufficient evidence of functional convergence without an evolutionary link. For each case, we compare enzymes which have identical Enzyme Commission numbers (i.e. catalyse the same reaction), but different identifiers in the CATH data resource (i.e. different folds). We focus on similarities between their sequence, structure, active site geometry, cofactors and catalytic mechanism. These features are then assessed to evaluate whether all the evidence on these structurally diverse proteins supports their independent evolution to catalyse the same chemical reaction. Our approach combines literature information with knowledge-based computational resources from, amongst others, M-CSA, PDBe and PDBsum, supported by tailor made software to explore active site structure and assess mechanism similarity. We find that there are multiple varieties of convergent functional evolution observed to date and it is necessary to investigate sequence, structure, active site geometry and enzyme mechanisms to describe such convergence accurately.
ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer’s disease
Authors: Egervari Gabor , Alexander Desi C. , Donahue Greg , Huang Hua , Hogan Connor , Mendoza Mariel , Garcia Benjamin A. , Bonini Nancy M. , Berger Shelley L.
Published: April 2024

Dysregulation of histone acetylation in the brain has emerged as a major contributor to human Alzheimer’s disease (AD). The mechanisms by which these protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is chromatin-associated in neurons. ACSS2 is recruited to specific promoters and generates a local pool of acetyl-CoA from acetate, thereby fueling histone acetylation and driving the expression of neuronal genes that regulate learning and memory. Here, we examine the contribution of ACSS2-mediated histone acetylation to AD-related molecular and behavioral outcomes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. Further, we identify Cajal-Retzius neurons as a critical hippocampal neuronal population affected, exhibiting the largest epigenetic and transcriptional dysregulation. Overall, these results reveal ACSS2 as a key neuroprotective metabolic enzyme, dysregulation of which might play an important role in the etiology of human AD, and guide the development of future therapies for AD and related dementia.
IL-1RA Disrupts ATP Activation of P2RX7 in Human Monocyte-Derived Microglia-like Cells
Authors: Heavener Kelsey , Kabra Khushbu , Yidenk Maedot , Bradshaw Elizabeth
Published: April 2024

The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer’s disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-drivenIL1βandIL18production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation ofIL1βandIL18expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-drivenIL1βandIL18gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.
Synergistic innate immune activation and anti-tumor immunity through combined STING and TLR4 stimulation
Authors: Higgs Emily F. , Gajewski Thomas F.
Published: April 2024

Previous work has shown that innate immune sensing of tumors involves the host STING pathway, which leads to IFN-β production, dendritic cell (DC) activation, and T cell priming against tumor antigens. This observation has led to the development of STING agonists as a potential cancer therapeutic. However, despite promising results in mouse studies using transplantable tumor models, clinical testing of STING agonists has shown activity in only a minority of patients. Thus, further study of innate immune pathways in anti-tumor immunity is paramount. Innate immune activation in response to a pathogen rarely occurs through stimulation of only one signaling pathway, and activating multiple innate immune pathways similar to a natural infection is one possible strategy to improve the efficacy of STING agonists. To test this, we performed experiments with the STING agonist DMXAA alone or in combination with several TLR agonists. We found that LPS + DMXAA induced significantly greater IFN-β transcription than the sum of either agonist alone. To explain this synergy, we assayed each step of STING pathway signaling. LPS did not increase STING protein aggregation, IRF3 phosphorylation, or IRF3 nuclear translocation beyond what occurred with DMXAA alone. However, since the IFN-β promoter also includes NF-κB binding sites, we additionally examined the NF-κB pathway. In fact, LPS increased the phosphorylation and nuclear translocation of the NF-κB subunit p65, and NF-κB signaling was required for the observed synergy. Intratumoral injection of suboptimal doses of LPS + DMXAA resulted in significantly improved tumor control of B16 melanoma in vivo compared to either agonist alone. Our results suggest that combinatorial signaling through TLR4 and STING results in optimal innate signaling via co-involvement of NF-κB and IRF3, and that combined engagement of these two pathways has therapeutic potential.
Human foot force reveals different balance control strategies between healthy younger and older adults
Authors: Shiozawa Kaymie , Sugimoto-Dimitrova Rika , Gruben Kreg G. , Hogan Neville
Published: April 2024

Aging can cause the decline of balance ability, which can lead to increased falls and decreased mobility. This work aimed to discern differences in balance control strategies between healthy older and younger adults. Foot force data of 38 older and 65 younger participants (older and younger than 60 years, respectively) were analyzed. To first determine whether the two groups exhibited any differences, this study incorporated the orientation of the foot-ground interaction force in addition to its point of application. Specifically, the frequency-dependence of the “intersection point” of the lines of actions of the foot-ground interaction force were evaluated. Results demonstrated that, like the mean center-of-pressure speed, a traditionally-employed measure, the intersection-point analysis could distinguish between the two participant groups. Then, to further explore age-specific control strategies, simulations of standing balance were conducted. An optimal controller stabilized a double-inverted-pendulum model with torque-actuated ankle and hip joints corrupted with white noise. The experimental data were compared to the simulation results to identify the controller parameters that best described the human data. Older participants showed significantly more use of the ankle than hip compared to younger participants. Best-fit controller gains suggested diminished intrinsic muscle stiffness in older adults, indicative of muscle strength loss, that was likely compensated by increased neural feedback. These results underscore the advantages of the intersection-point analysis to quantify shifts in interjoint control strategies with age, thus highlighting its potential to be used as a balance assessment tool in research and clinical settings.

NEW & NOTEWORTHY

Age groups were distinguished by analyzing foot-ground force data during quiet standing in older and younger adults to calculate the foot-force vector intersection point that emerges across frequency bands. Modeling balance and comparing the simulations’ outcomes with experimental results suggested that older adults increased reliance on neural feedback, possibly compensating for muscle strength deficiency. This novel analysis also quantified controllers for each participant, highlighting its potential to be implemented as a balance assessment tool.
Drug-loaded nanoparticles for cancer therapy: a high-throughput multicellular agent-based modeling study
Authors: Wang Yafei , Bucher Elmar , Rocha Heber , Jadhao Vikram , Metzcar John , Heiland Randy , Frieboes Hermann B. , Macklin Paul
Published: April 2024

Interactions between biological systems and engineered nanomaterials have become an important area of study due to the application of nanomaterials in medicine. In particular, the application of nanomaterials for cancer diagnosis or treatment presents a challenging opportunity due to the complex biology of this disease spanning multiple time and spatial scales. A system-level analysis would benefit from mathematical modeling and computational simulation to explore the interactions between anticancer drug-loaded nanoparticles (NPs), cells, and tissues, and the associated parameters driving this system and a patient’s overall response. Although a number of models have explored these interactions in the past, few have focused on simulating individual cell-NP interactions. This study develops a multicellular agent-based model of cancer nanotherapy that simulates NP internalization, drug release within the cell cytoplasm, “inheritance” of NPs by daughter cells at cell division, cell pharmacodynamic response to the intracellular drug, and overall drug effect on tumor dynamics. A large-scale parallel computational framework is used to investigate the impact of pharmacokinetic design parameters (NP internalization rate, NP decay rate, anticancer drug release rate) and therapeutic strategies (NP doses and injection frequency) on the tumor dynamics. In particular, through the exploration of NP “inheritance” at cell division, the results indicate that cancer treatment may be improved when NPs are inherited at cell division forcytotoxicchemotherapy. Moreover, smaller dosage ofcytostaticchemotherapy may also improve inhibition of tumor growth when cell division is not completely inhibited.

This work suggests that slow delivery by “heritable” NPs can drive new dimensions of nanotherapy design for more sustained therapeutic response.
Genomic surveillance reveals that the dengue 2 virus lineage responsible for the 2023-2024 epidemic in the French Caribbean Islands is resistant to Mosnodenvir
Authors: Bouzidi Hawa Sophia , Sen Selin , Piorkowski Géraldine , Pezzi Laura , Ayhan Nazli , Fontaine Albin , Canivez Thomas , Gueulen Manon , Amaral Rayane , Grard Gilda , Durand Guillaume André , de Lamballerie Xavier , Touret Franck , Klitting Raphaëlle
Published: April 2024

Dengue fever is the most important arbovirosis for public health, with more than 5 million cases worldwide in 2023. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. Here, by analyzing dengue virus (DENV) genomes from the ongoing epidemic in the French Caribbean Islands, we show that they all exhibit mutation NS4B:V91A, previously associated with strong resistance to mosnodenvirin vitro. Using antiviral activity tests on clinical and reverse-genetic strains, we confirm a 600-fold decrease in mosnodenvir sensitivity. Finally, combining phylogenetic analysis and experimental testing for resistance, we find that the V91A resistance mutation likely emerged multiple times over the last 30 years in DENV-2 and DENV-3. These results call for increased genomic surveillance, in particular to track lineages with resistance mutations. These efforts should allow to better assess the activity profile of DENV treatments in development against circulating strains.
Splitting ratio in sevoflurane vapouriser-a relook on calculations
Authors: Menon D Girijanandan , George Manjit , Salim Salih V , Sreekumar R. , Philip Sam , Mathew Roshin K , Bju Princymol , Mathai Merin Helen
Published: April 2024

Textbooks of anaesthesia describe in detail the calculations associated with splitting ratios created invariable bypass vapourisers. These calculations are based on assumptions of carrier gas flow (eg:assume 150 ml) as practised withmeasured flow vaporizers[1,2]. Carrier gas flow in a variable bypass vaporizer is agent specific,dynamic,unknown and operator independent.Therefore assuming carrier gas flow in calculations related to variable bypass vaporisers is without rationale[3]. In spite of technological advance,the amount of vapour produced is calculated based on clinically impractical assumptions. A simple method and formula is suggested for the quick estimate of vapour output, carrier gas flow and determine the splitting ratio while operating a sevoflurane variable bypass vaporizer.
The intracellular bacteriumOrientia tsutsugamushihijacks the adaptor protein BICD2 for dynein-based motility
Authors: Manigrasso Giulia , Saharat Kittirat , Kullapanich Chitrasak , Boulanger Jerome , Morgan Tomos E. , Kramer Holger , Salje Jeanne , Carter Andrew P.
Published: April 2024

The intracellular bacteriumOrientia tsutsugamushirelies on the microtubule cytoskeleton and the motor protein dynein to traffic to the perinuclear region within infected cells. However, it remains unclear how the bacterium is coupled to the dynein machinery and how transport is regulated. Here, we discover thatO. tsutsugamushiuses its autotransporter protein ScaC to recruit the dynein adaptor BICD2 to the bacterial surface. We show that ScaC is sufficient to engage dynein-based motility in the absence of other bacterial proteins and that BICD2 is required for efficient movement ofO. tsutsugamushiduring infection. Using TIRF single-molecule assays, we demonstrate that ScaC induces BICD2 to adopt an open conformation which activates the assembly of dynein-dynactin complexes. Our results reveal a novel role for BICD2 during bacterial infection and provide mechanistic insights into the life cycle of an important human pathogen.
Novel roles for pirin proteins and a 2-ketoglutarate: ferredoxin oxidoreductase ortholog inBacteroides fragiliscentral metabolism and comparison of metabolic mutants susceptibility to metronidazole and amixicile
Authors: Gough Andrea M. , Parker Anita C. , O’Bryan Patricia J. , Whitehead Terence R. , Roy Sourav , Garcia Brandon L. , Hoffman Paul S. , Jeffrey Smith C. , Rocha Edson R.
Published: April 2024

The regulation of the central metabolism and fermentation pathways and its effect on antimicrobial susceptibility in the anaerobic pathogenBacteroides fragilisis not completely understood. In this study we show thatB. fragilisencodes for two iron-dependent redox-sensitive regulatory pirin protein genes,pir1andpir2,whose mRNA expression are upregulated following oxygen exposure and growth in iron-limiting conditions.Δpir1andΔpir2mutants showed altered short-chain fatty acids production compared to the parent strain. Overexpression of Pir1 and Pir2 increased susceptibility to metronidazole (MTZ), and to amixicile (AMIX), a novel inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobes. We hypothesized these observations were a result of a modulatory effect of Pir1 and Pir2 proteins. Consistent with this, we showed that Pir1 forms direct protein-protein interactions with PFOR. In addition, AlphaFold2-based structural analysis predicts that Pir1 and Pir2 form stable interactions with several enzymes of the central metabolism including the 2-ketoglutate:ferredoxin oxidoreductases (KFOR), Kor1AB and Kor2CDAEBG. A series of metabolic mutants and electron transport chain inhibitors were used to show a wide-ranging effect of bacterial metabolism on MTZ and AMIX susceptibility. There was no cross-resistance between MTZ resistant strains with AMIX susceptibility. Furthermore, we show that AMIX is an effective antimicrobial againstB. fragilisin an experimental model of intra-abdominal infection. This investigation led to the discovery that thekor2AEBGgenes are essential for growth, and we present evidence thatkor2AEBGgenes have dual-functions including the reductive synthesis of 2-ketoglutarate via reverse TCA cycle. Support for a novel Kor2AEBG activity comes from the findings showing that addition of compounds containing oleic acid stimulated growth of theΔkor2AEBGmutant. However, the metabolic activity that bypasses KorAEBG function remains to be defined. Collectively our investigation reveals new information onB. fragiliscentral metabolism and its modulatory control by pirin proteins. These data provide new genetic and metabolic knowledge which may be leveraged for the future development of new narrow-spectrum antimicrobials.
Molecular interplay between HURP and Kif18A in mitotic spindle regulation
Authors: Perez-Bertoldi Juan M. , Zhao Yuanchang , Thawani Akanksha , Yildiz Ahmet , Nogales Eva
Published: April 2024

During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imagingin vitro, we demonstrate that Kif18A motility is regulated by HURP. While sparse decoration of HURP activates the motor, higher concentrations hinder processive motility. To shed light on this behavior, we determined the binding mode of HURP to microtubules using Cryo-EM. The structure reveals that one HURP motif spans laterally across β-tubulin, while a second motif binds between adjacent protofilaments. HURP partially overlaps with the microtubule-binding site of the Kif18A motor domain, indicating that excess HURP inhibits Kif18A motility by steric exclusion. We also observed that HURP and Kif18A function together to suppress dynamics of the microtubule plus-end, providing a mechanistic basis for how they collectively serve in spindle length control.
Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4
Authors: Mohd Saif , Oder Andreas , Specker Edgar , Neuenschwander Martin , Von Kries Jens Peter , Daumke Oliver
Published: April 2024

Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain-containing proteins (EHDs) comprise a family of eukaryotic dynamin-related ATPases that participate in various endocytic membrane trafficking pathways. Dysregulation of EHDs function has been implicated in various diseases, including cancer. The lack of small molecule inhibitors which acutely target individual EHD members has hampered progress in dissecting their detailed cellular membrane trafficking pathways and their function during disease. Here, we established a Malachite green-based assay compatible with high throughput screening to monitor the liposome-stimulated ATPase of EHD4. In this way, we identified a drug-like molecule that inhibited EHD4’s liposome-stimulated ATPase activity. Structure activity relationship (SAR) studies indicated sites of preferred substitutions for more potent inhibitor synthesis. Moreover, the assay optimization in this work can be applied to other dynamin family members showing a weak and liposome-dependent nucleotide hydrolysis activity.